Clinical phenotypes of adult-onset Behçet's syndrome: a comprehensive cross-sectional study in China.

Behçet's syndrome (BS) is a variant vasculitis that can involve multiple organs with inflammatory manifestations. This study aimed to provide a more comprehensive analysis of the clinical phenotypes and characteristics of BS patients. We enrolled 2792 BS patients referred from China nationwide to Huadong Hospital Affiliated to Fudan University from October 2012 to December 2022. Detailed assessments of demographic information, clinical manifestations, laboratory results, gastroscopy, and medical imaging were conducted. Cluster analysis was performed based on 13 variables to determine the clinical phenotypes, and each phenotype was characterized according to the features of BS patients. A total of 1834 BS patients were included, while 958 invalid patients were excluded. The median age at onset was 31 years (IQR, 24-40 years), and the median disease duration was 10 years (IQR, 5-15 years). Eight clusters were identified, including mucocutaneous (n = 655, 35.7%), gastrointestinal (n = 363, 19.8%), articular (n = 184, 10%), ocular (n = 223, 12.2%), cardiovascular (n = 119, 6.5%), neurological (n = 118, 6.4%), vascular (n = 114, 6.2%), and hematological phenotype (n = 58, 3.2%). Ocular (RR = 1.672 (95% CI, 1.327-2.106); P < 0.001), gastrointestinal (RR = = 1.194 (95% CI, 1.031-1.383); P = 0.018), cardiovascular (RR = = 2.582 (95% CI, 1.842-3.620); P < 0.001), and vascular (RR = = 2.288 (95% CI, 1.600-3.272); P < 0.001) involvement were more prevalent in male BS patients, while the hematological (RR = 0.528 (95% CI, 0.360-0.776); P = 0.001) involvement was more common among female patients. BS presents significant heterogeneity and gender differences. The eight phenotypes of BS patients we propose hold the potential to assist clinicians in devising more personalized treatment and follow-up strategies. Key Points • This cluster analysis divided adult-onset BS into eight clinical phenotypes. • BS demonstrates a high level of clinical heterogeneity and gender differences. • Hematologic phenotypes of BS present distinctive clinical characteristics.

miR-141-3p attenuates RSL3-induced ferroptosis and intestinal epithelial-mesenchymal transition via directly inhabits ZEB1 in intestinal Behçet's syndrome.

The aims of this study were to investigate whether the ferroptosis is involved in intestinal Behçet's syndrome (IBS), and to identify if miR-141-3p could attenuate RAS-selective lethal 3 (RSL3)-induced ferroptosis and intestinal epithelial to mesenchymal transition (EMT) via directly inhabits zinc fnger E-box binding homeobox 1 (ZEB1). The expressions of ferroptosis-related proteins in the intestinal tissues of patients with IBS were investigated by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Malondialdehyde (MDA) contents of the intestinal tissues and cells were detected. Serum from IBS patients and RSL3 were co-cultured with intestinal epithelial cells in vitro. In order to investigate whether RSL3-induced ferroptosis can be ameliorated by miR-141-3p, the intestinal epithelial cells were firstly stimulated with RSL3 and then incubated with miR-141-3p mimics. Western blot was used to measure the expression of EMT and ferroptosis-related proteins. Expression of GPX4 (22.51% ± 2.05%, 51.75% ± 3.47%, t = - 7.77, p = 0.000) and xCT (17.49% ± 1.57%, 28.73% ± 1.75%, t = - 4.38, p = 0.003) were significantly lower in intestinal mucosal tissues of patients with IBS compared with HC group. Compared with the HC samples, the IBS specimens had significantly higher MDA (t = 4.32, p = 0.01). Moreover, the relative mRNA levels of ferritin light chain (FTL) (t = 4.07, p = 0.02) and ferritin heavy chain (FTH) (t = 8.82, p = 0.001) in the intestinal tissues were significant higher in IBS patients than in HC group. Serum from IBS patients could induce intestinal epithelial cell ferroptosis in vitro. Moreover, miR-141-3p could attenuate intestinal epithelial cell ferroptosis-induced by RSL3 and intestinal EMT via targeting ZEB1 in vitro. Ferroptosis were induced in patients with IBS. Moreover, the serum from IBS patients could induce ferroptosis in vitro. miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1. Therefore, miR-141-3p may open new avenues for the treatment of IBS in the future. Key Points • Ferroptosis in IBS is first reported in this study. • In this study, we explored that the serum from IBS patients could induce ferroptosis in vitro and miR-141-3p could attenuate intestinal epithelial cell ferroptosis and intestinal EMT via targeting ZEB1.

PLK1-activating IFI16-STING-TBK1 pathway induces apoptosis of intestinal epithelial cells in patients with intestinal Behçet's syndrome.

Inflammatory signals from immunological cells may cause damage to intestinal epithelial cells (IECs), resulting in intestinal inflammation and tissue impairment. Interferon-γ-inducible protein 16 (IFI16) was reported to be involved in the pathogenesis of Behçet's syndrome (BS). This study aimed to investigate how inflammatory cytokines released by immunological cells and IFI16 participate in the pathogenesis of intestinal BS. RNA sequencing and real-time quantitative PCR (qPCR) showed that the positive regulation of tumor necrosis factor-α (TNF-α) production in peripheral blood mononuclear cells (PBMCs) of intestinal BS patients may be related to the upregulation of polo like kinase 1 (PLK1) in PBMCs (P = 0.012). The plasma TNF-α protein level in intestinal BS was significantly higher than in healthy controls (HCs; P = 0.009). PBMCs of intestinal BS patients and HCs were co-cultured with human normal IECs (NCM460) to explore the interaction between immunological cells and IECs. Using IFI16 knockdown, PBMC-NCM460 co-culture, TNF-α neutralizing monoclonal antibody (mAb), stimulator of interferon genes (STING) agonist 2'3'-cGAMP, and the PLK1 inhibitor SBE 13 HCL, we found that PLK1 promotes the secretion of TNF-α from PBMCs of intestinal BS patients, which causes overexpression of IFI16 and induces apoptosis of IECs via the STING-TBK1 pathway. The expressions of IFI16, TNF-α, cleaved caspase 3, phosphorylated STING (pSTING) and phosphorylated tank binding kinase 1 (pTBK1) in the intestinal ulcer tissue of BS patients were significantly higher than that of HCs (all P < 0.05). PLK1 in PBMCs of intestinal BS patients increased TNF-α secretion, inducing IEC apoptosis via activation of the IFI16-STING-TBK1 pathway. PLK1 and the IFI16-STING-TBK1 pathway may be new therapeutic targets for intestinal BS.

Clinical heterogeneity and five phenotypes identified in pediatric Behçet's syndrome: a cohort study from Shanghai Behçet's syndrome database.

OBJECTIVES: Behçet's syndrome (BS) is a rare disease of unknown etiology, with limited reports especially in pediatric BS. The clinical characteristics and phenotypes of pediatric BS as a highly heterogeneous variable vessel vasculitis were investigated in this study. METHODS: A cross-sectional study was conducted to compare clinical variables and descriptive characteristics of BS by age of onset and gender. Cluster analysis was then performed to identify the phenotypes of pediatric BS. RESULTS: A total of 2082 BS patients were included in this study, 1834 adults and 248 children. Compared with adult-onset BS, pediatric BS had a higher incidence of folliculitis [relative risks (RR) and 95% confidence interval (CI) 1.3 (1.0-1.5)], uveitis of the left eye [RR and 95% CI 2.3 (1.0-5.0)], intestinal ulcer complications [RR and 95% CI 2.1 (1.1-4.2)], pericarditis [RR and 95% CI 2.5 (1.0-6.2)], and psychiatric disorders [RR and 95% CI 2.8(1.0-7.9)], while the incidence of thrombocytopenia was lower [RR 0.2 (0.1-1.0)]. Among pediatric BS, females had more genital ulcers, while males were more likely to have skin lesions, panuveitis, vascular involvement, venous lesions, cardiac involvement, and aortic aneurysms. Cluster analysis classified pediatric BS into five clusters (C1-C5): C1 (n = 61, 24.6%) showed gastrointestinal (GI) involvement; C2 (n = 44, 17.7%) was the central nervous system (CNS) type where 23 cases overlapped joint involvement; in C3 (n = 35, 14.1%), all patients presented with arthritis or arthralgia; all patients in C4 (n = 29, 11.7%) manifested ocular involvement, with a few patients overlapping with GI involvement or joint damage; C5 (n = 79, 31.9%) was the mucocutaneous type, presenting both oral ulcers, genital ulcers, and skin lesions. CONCLUSIONS: The clinical features of pediatric and adult BS differ significantly. Male and female pediatric BS also have a distinct demography. Five phenotypes including GI, CNS, joint, ocular, and mucocutaneous types were identified for pediatric BS.

The roles of immune cells in Behçet's disease.

Behçet's disease (BD) is a systemic vasculitis that can affect multiple systems, including the skin, mucous membranes, joints, eyes, gastrointestinal and nervous. However, the pathogenesis of BD remains unclear, and it is believed that immune-inflammatory reactions play a crucial role in its development. Immune cells are a critical component of this process and contribute to the onset and progression of BD. By regulating the function of these immune cells, effective control over the occurrence and development of BD can be achieved, particularly with regards to monocyte activation and aggregation, macrophage differentiation and polarization, as well as T cell subset differentiation. This review provides a brief overview of immune cells and their role in regulating BD progression, which may serve as a theoretical foundation for preventing and treating this disease.

Comprehensive analysis of T-cell receptor repertoires reveals antigen-driven T-cell clusters in patients with Behçet's syndrome.

T lymphocytes are the major components of adaptive immunity in Behçet's syndrome (BS) pathology. However, the precise mechanism of T-cell-induced inflammatory condition remains to be determined. We applied bulk sequencing of the T-cell receptor (TCR) ß chain in peripheral blood samples from 45 patients with BS and 10 healthy donors as controls. TCR repertoires in BS patients displayed more clonality and less diversity than in healthy donors. Male patients exhibited lower diversity metrics of TCR and had a larger proportion in the top 10 clones than females (p = 0.016). There were no TCR clonality differences in other clinical features, such as age, disease duration, organ involvement, disease severity, and activity. By "Grouping of Lymphocyte Interactions by Paratope Hotspots" (GLIPH2) for antigen prediction, we found distinct 2477 clusters of TCR-ß sequences that potentially recognize similar antigens shared between BS patients. We observed clonal T-cell expansion in BS patients. Sexual differences in TCR clonal expansion and public TCR groups deserve further study to reveal the underline T-cell-mediated immunity in BS.

Predictors of infliximab refractory intestinal Behçet's syndrome: A retrospective cohort study from the Shanghai Behçet's syndrome database.

OBJECTIVES: This retrospective cohort study aimed to find out predictors and early biomarkers of Infliximab (IFX) refractory intestinal Behçet's syndrome (intestinal BS). METHODS: We collected the baseline clinical characteristics, laboratory parameters, and concomitant therapies of intestinal BS patients treated by IFX from the Shanghai Behçet's syndrome database. After 1 year IFX therapy, intestinal BS patients with non-mucosal healing (NMH, intestinal ulcers detected by colonoscopy) and/or no clinical remission [NCR, scores of the disease activity index for intestinal Behçet's disease (DAIBD) ≥20] were defined as IFX refractory intestinal BS. Multivariate logistic regression analysis was performed to evaluate the predictors for NMH and NCR in IFX refractory intestinal BS. RESULTS: In 85 intestinal BS patients, NMH was identified in 29 (34.12%) patients, and NCR was confirmed in 20 (23.53%) patients. Erythrocyte sedimentation rate (ESR; ≥24 mm/h) and free triiodothyronine (fT3; ≤3.3pmol/L) were the independent risk factors of NMH in IFX refractory intestinal BS. Drinking alcohol and the fT3/free thyroxine ratio (fT3/fT4; ≤0.24) were independent risk factors, and thalidomide was an independent protective factor, for NCR in intestinal BS patients treated by IFX. CONCLUSION: This study may be applicable for adjusting the therapeutic strategy and sidestepping unnecessary exposure to IFX in intestinal BS patients. Routine assessments of ESR, fT3, and fT3/fT4 ratio are helpful to identify high-risk individuals of IFX refractory intestinal BS. Thalidomide is suggested to be a concomitant therapy with IFX for intestinal BS patients.

The roles of immune cells in Behçet's disease

Abstract Behçet's disease (BD) is a systemic vasculitis that can affect multiple systems, including the skin, mucous membranes, joints, eyes, gastrointestinal and nervous. However, the pathogenesis of BD remains unclear, and it is believed that immune-inflammatory reactions play a crucial role in its development. Immune cells are a critical component of this process and contribute to the onset and progression of BD. By regulating the function of these immune cells, effective control over the occurrence and development of BD can be achieved, particularly with regards to monocyte activation and aggregation, macrophage differentiation and polarization, as well as T cell subset differentiation. This review provides a brief overview of immune cells and their role in regulating BD progression, which may serve as a theoretical foundation for preventing and treating this disease.

Tofacitinib as an alternative therapy for refractory intestinal Behçet's syndrome.

Background: Intestinal Behçet's syndrome is a major cause of morbidity and mortality in Behçet's syndrome. Objectives: Current treatment challenges remain in refractory intestinal Behçet's syndrome, when patients failed first and second-line therapies. Design: We reported the efficacy and safety profiles of tofacitinib in patients with moderate-severe intestinal Behçet's syndrome in a retrospective single-center study. Methods: Treatment with glucocorticoids, immunosuppressors, or even anti-TNFα monoclonal antibodies (mAbs) had previously failed. Primary outcomes were clinical remission or low disease activity and endoscopic healing. Results: We included 13 patients; 11 were administered tofacitinib 5 mg twice daily, and 2 took tofacitinib 5 mg once daily. Nine patients achieved clinical remission after a mean treatment duration of 10.1 ± 7.0 months, and the other four had low disease activity. Follow-up endoscopy was available in 11 patients: 5 had achieved mucosal healing; the other 4 achieved marked mucosal improvement. Prednisone dosage was significantly reduced, from 30 (interquartile range: 20-30) mg/d to 2.5 (interquartile range: 0-12.5) mg/d (p < 0.001). No serious adverse event was observed. Conclusion: Tofacitinib could be an efficacious and generally well-tolerated option in patients with intestinal Behçet's syndrome refractory to conventional agents, even anti-TNFα mAbs.

Clinical heterogeneity of ocular Behçet's syndrome versus intestinal Behçet's syndrome: a cross-sectional study from Shanghai Behçet's syndrome database.

BACKGROUND: Behçet's syndrome (BS) is a rare variant vasculitis which can involve the eyes and gastrointestinal systems. However, ocular involvement rarely overlaps with intestinal lesions. This study aimed to compare the clinical characteristics and laboratory parameters of ocular BS and intestinal BS patients in China and analyze the differences between two key phenotypes to verify the heterogeneous conditions in BS patients. METHODS: A retrospective analysis was used to collect the demographic data, clinical characteristics, endoscopic findings, and laboratory parameters from 135 ocular BS and 174 intestinal BS patients. The Mann-Whitney U test and Pearson chi-square or continuity correction was used to analyze the differences between two groups. RESULTS: Among 916 BS patients enrolled in this study, ocular BS and intestinal BS accounted for 14.74% (135 cases) and 19.00% (174 cases), respectively. Ocular and intestinal involvements overlapped in only 7 cases (0.76%). Male gender (74.8% vs. 51.1%, P=0.00), erythema nodosum (45.9% vs. 32.2%, P=0.01), and vascular involvement (6.7% vs. 1.7%, P=0.03) were more frequent in the ocular BS group compared with the intestinal BS group. On the contrary, hematologic involvement (7.5% vs. 0.0%, P=0.00) and fever (17.8% vs. 4.4%, P=0.00) were more frequent in the intestinal BS group compared with the ocular BS group. Additionally, the inflammation markers including ESR [26.5 (16.0-41.5) vs. 9.0 (5.0-15.0) mm/H, P=0.00], CRP [14.8 (4.8-33.0) vs. 4.1 (1.6-8.3) mg/L, P=0.00], serum amyloid A [27.4 (10.8-92.3) vs. 11.3 (6.0-24.0) mg/L, P=0.00], and interleukin 6 [8.4 (1.7-18.7) vs. 1.7 (1.5-3.2) pg/mL, P=0.00] were higher in the intestinal BS group than those in the ocular BS group, respectively. CONCLUSIONS: Ocular BS was more prevalent in male patients and more likely to manifest with erythema nodosum and vascular involvement, while intestinal BS tends to have fever and hematologic disorders with higher inflammation markers. Ocular BS and intestinal BS are two distinct clinical phenotypes and very rarely overlapped.

Expression of miRNAs derived from plasma exosomes in patients with intestinal Behçet's syndrome.

OBJECTIVES: MicroRNAs (miRNAs) derived from plasma exosomes are potential diagnostic biomarkers. However, little is known about the expression of miRNAs derived from plasma exosomes in patients with intestinal Behçet's syndrome (BS). This study aimed to explore the difference of miRNAs derived from plasma exosomes between intestinal BS patients and healthy people, and further identify potential biomarkers that predict the disease activity of intestinal BS. METHODS: A total of 43 intestinal BS patients and 23 healthy volunteers were enrolled, among whom 23 were active intestinal BS and 20 were stable intestinal BS. The miRNAs expression profiles of plasma exosomes in 3 active intestinal BS patients and 3 healthy volunteers were determined using next-generation high throughput sequencing. Additionally, significantly differentially expressed miRNAs were further analysed by quantitative real-time polymerase chain reaction (qRT-PCR) in a validation cohort of 60 subjects. RESULTS: From the sequencing analysis, 15 miRNAs were identified to be differently expressed (p<0.05). Of these, 13 miRNAs were up-regulated, and 2 were down-regulated in intestinal BS patients compared with healthy volunteers. Furthermore, qRT-PCR analysis confirmed that miR-141-3p was down-regulated and miR-122-5p, miR-150-3p, miR-183-5p, miR-224-5p and miR-342-5p were up-regulated in intestinal BS patients' plasma exosomes. Additionally, the level of miR-141-3p was negatively correlated with disease activity indicators of intestinal BS, while miR-122-5p, miR-150-3p, miR-183-5p, miR-224-5p and miR-342-5p was positively correlated with disease activity indicators of intestinal BS. CONCLUSIONS: Circulating miR-141-3p, miR-122-5p, miR-150-3p, miR-183-5p, miR-224-5p and miR-342-5p derived from plasma exosomes may serve as biomarkers of disease activity in intestinal BS.

New insight into the features of Behçet's disease with gastrointestinal ulcer: a cross-sectional observational study.

BACKGROUND: Behçet's disease (BD) can involve any site of the alimentary canal. There has been research concerning intestinal BD. Nevertheless, the entire digestive tract not yet been studied extensively. Therefore, the purpose of study was to describe the prevalence, location, clinical features and possible risk factors of BD with gastrointestinal tract ulcer. METHODS: This was a cross-sectional observational study that included 1232 consecutive BD patients who routinely underwent endoscopy upon their wishes. The clinical symptoms, endoscopic findings, and histologic features of BD with gastrointestinal ulcer and negative Helicobacter pylori (Hp) were identified. RESULT: We found that 22.16% (273/1232) BD patients had ulcers of the alimentary tract. At presentation, 61.54% (168/273) patients were asymptomatic. Isolated gastroduodenal involvement is an extremely usual event. The second was the pairwise combination between bowel segments, and 24 cases involved three segments at the same time. One patient suffered from total gastrointestinal tract involvement. Inflammation was the most common histopathologic feature 77.60% (142/183). The 273 BD patients with gastrointestinal ulcer were at greater risk of having archenteric symptoms (OR 0.070, P < 0.001), fever (OR 0.115, P = 0.047), high CRP (OR 0.994, P = 0.027) and BDCAF level (OR 0.590, P = 0.010). Uveitis correlates negatively with gastrointestinal involvement in BD patients (OR 3.738, P = 0.011). CONCLUSIONS: BD could affect the upper gastrointestinal tract independently. Endoscopy should be conducted in all patients in whom a diagnosis of BD is entertained, especially in patients with higher CRP, disease activity and fever. While, BD patients with uveitis correlates negatively with gastrointestinal involvement.

Epidemiology of Takayasu arteritis in Shanghai: A hospital-based study and systematic review.

BACKGROUND: Takayasu arteritis (TAK) is a rare large vessel vasculitis, and epidemiological data on TAK are lacking in China. Thus, we designed this study to estimate the TAK prevalence and incidence in residential Shanghai, China. METHODS: Data on diagnosed TAK cases aged over 16 years were retrieved from 22 tertiary hospitals in Shanghai through hospital electronic medical record systems between January 1, 2015 and December 31, 2017 to estimate the prevalence and incidence. A systematic literature review based on searches in PubMed, Ovid-Medline, Excerpta Medica Database (EMBASE), Web of Science, and China National Knowledge Infrastructure (CNKI) was performed to summarize TAK distribution across the world. RESULTS: In total 102 TAK patients, with 64% female, were identified. The point prevalence (2015-2017) was 7.01 (95% CI 5.65-8.37) cases per million, and the mean annual incidence was 2.33 (1.97-3.21) cases per million. The average age of TAK patients was 44 ± 16 years, with the highest prevalence (11.59 [9.23-19.50] cases per million) and incidence (3.55 [0.72 3.74] cases per million) in the 16 to 34 years population. Seventeen reports were included in the system review, showing that the epidemiology of TAK varied greatly across the world. The incidence and prevalence were both relatively higher in Asian countries, with the prevalence ranging 3.3-40 cases per million and annual incidence ranging 0.34-2.4 cases per million. CONCLUSIONS: The prevalence and incidence of TAK in Shanghai was at moderate to high levels among the previous reports. The disease burden varied globally among racial populations.

Plasma exosomes derived from patients with intestinal Behçet's syndrome induce intestinal epithelial cell pyroptosis.

OBJECTIVES: Intestinal Behçet's syndrome (IBS) has high morbidity and mortality rates with serious complications. The purpose of this study was to investigate the expression of pyroptosis-related proteins in the intestinal tissues of IBS patients and explore the role of plasma exosomes derived from IBS patients in the pyroptosis of intestinal epithelial cells. METHOD: Immunohistochemistry was used to investigate the expression of nucleotide-binding domain-like receptor protein 3 (NLRP3), caspase-1, and gasdermin D (GSDMD). Quantitative real-time PCR was employed to measure the mRNA levels of IL-1ß and IL-18 in the intestinal tissues. Plasma exosomes were isolated and observed by transmission electron microscopy. The exosomes were co-cultured with intestinal epithelial cells in vitro. Western blot was used to measure the expression of pyroptosis-related proteins including NLRP3, full-length GSDMD, N-terminal GSDMD, pro-caspase-1, and cleaved caspase-1. The levels of IL-1ß and IL-18 were detected by enzyme-linked immunosorbent assay. Cell death was measured by using the lactate dehydrogenase (LDH) release assay. RESULTS: Expression of NLRP3 (12.2% ± 1.2%, 8.1% ± 0.9%, t = 4.692, p = 0.009), caspase-1 (24.6% ± 2.1%, 4.2% ± 1.8%, t = 12.842, p = 0.000), and GSDMD (16.6% ± 1.9%, 9.8% ± 1.3%, t = 5.194, p = 0.007) were significantly increased in the intestinal tissues of patients with IBS compared with normal control (NC) group, respectively. The relative mRNA levels of IL-1ß (t = 4.308, p = 0.005) and IL-18 (t = 3.096, p = 0.021) in the intestinal tissues were significantly higher in IBS patients than in NC group, while the protein levels of IL-1ß (t = 3.873, p = 0.018) and IL-18 (t = 4.389, p = 0.012) were also significantly increased, which was consistent with the results of the relative mRNA levels. Moreover, we found that exosomes from IBS patients significantly induced pyroptosis of intestinal epithelial cells via the activation of NLRP3 inflammasome in vitro experiments. CONCLUSIONS: Plasma exosomes derived from IBS patients may induce pyroptosis of intestinal epithelial cells via the activation of NLRP3 inflammasome. Key Points •The role of exosomes in IBS is first reported in this study. • In this study, we explored the mechanism that plasma exosomes derived from IBS patients may induce pyroptosis of intestinal epithelial cells via the activation of NLRP3 inflammasome.

Clinical characteristics and risk factors of intestinal involvement in Behçet's syndrome patients: a cross-sectional study from a single center.

BACKGROUND: Intestinal Behçet's syndrome (BS) has high morbidity and mortality rates with serious complications. The purpose of this study was to investigate the clinical characteristics and laboratory parameters of intestinal and mucocutaneous BS patients and analyze the risk factors of intestinal involvement in BS patients. METHODS: A retrospective analysis was used to collect the demographic data and laboratory parameters from 97 intestinal and 154 mucocutaneous BS patients. Univariate and multivariate logistic regression analyses were used to investigate the risk factors of intestinal involvement in BS patients. RESULTS: The most common clinical manifestations of first onset in intestinal BS patients were oral ulceration (100.00%), followed by genital ulcers (62.89%) and erythema nodule (28.87%), gastrointestinal lesions (28.87%), pseudofolliculitis (25.77%), fever (17.53%), arthritis (16.49%), ocular involvement (5.15%), while the least common were vascular involvement (2.06%) and hematologic involvement involvement (2.06%). The most common intestinal segment involved in intestinal BS patients was terminal ileum (30.9%), followed by ileocecal (18.6%), colon (15.5%). By univariate logistic regression analysis, gender, age at hospitalization, age of disease onset, BDCAF, T-SPOT, fever, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), leukocyte, erythrocyte, hemoglobin (HGB), neutrophil-to-lymphocyte ratio, serum amyloid A, complement 3, albumin, total cholesterol, high-density lipoprotein and interleukin 6 (IL-6) were found all risk factors of intestinal involvement in BS patients (P < 0.05 or P = 0.00). Moreover, gender (male), BDCAF (≥ 2), ESR (≥ 15 mm/H), CRP (> 10 mg/L), HGB (< 130 g/L) and IL-6 (> 7 pg/ml) were found the independent risk factors of intestinal involvement in BS patients (all P < 0.05). CONCLUSIONS: More attention shall be paid to gender, BDCAF, ESR, CRP, HGB and IL-6 in BS patients. When gender (male), BDCAF (≥ 2), ESR (≥ 15 mm/H), CRP (> 10 mg/L), HGB (< 130 g/L) and IL-6 (> 7 pg/ml) being observed, it may reminds that the presence of intestinal involvement in BS patients.

Distinct clinical characteristics of pediatric Behçet's syndrome: A study from a referral center in China.

OBJECTIVES: To describe the clinical features and patterns of phenotype aggregation in pediatric Behçet's syndrome (BS) in a tertiary center in China. METHODS: This was a cross-sectional study of consecutive BS patients in Huadong Hospital, Fudan University between September 2012 and January 2020. Pediatric BS was defined as diagnosed before 16 years old. We compared clinical variables between pediatric and adult patients. We calculate relative risks (RRs) of clinical variables according to sex. Moreover, a hierarchical cluster analysis was undertaken according to 29 clinical variables to determine homogeneous subgroups. RESULTS: From 1596 consecutive BS cases, we identified 69 pediatric BS. Compared with adult-diagnosed BS, pediatric-diagnosed patients had a higher frequency of folliculitis [RR 1.57 (95% CI 1.12, 2.20)], a lower frequency of arthralgia [RR 0.15 (95% CI 0.02, 1.07)] and panuveitis [RR 0.43 (95% CI 0.18, 1.03)], no cardiac lesion. There was an association between male and arterial thrombosis or aneurysms (p = .006). A cluster analysis stratified three sub-clusters (C1-C3): C1 (n = 30) showed a disease type merely affecting skin and mucosa. C2 (n = 20) represented the gastrointestinal type; most patients presented with intestinal involvement, and two cases with esophageal ulcers. In C3 (n = 19), showing a mixture of uveitis, vascular and central nervous system (CNS) involvement, six patients presented with uveitis and nine had vascular lesions, and three cases had CNS lesions. CONCLUSION: We conducted a comprehensive statistical analysis in a cohort of pediatric patients with BS in China. Less ocular involvement and no cardiac lesions were observed in childhood-diagnosed patients. For the first time, three distinct phenotype subgroups in pediatric-diagnosed patients were identified by cluster analysis.Key messagesThis study demonstrated the phenotype discrepancy between childhood and adult-diagnosed BS.Three distinct clusters were identified, with skin-mucosa, gastrointestinal, panuveitis, vascular and CNS subgroups.

Characteristics and phenotype heterogeneity in late-onset Behçet's syndrome: a cohort from a referral center in China.

OBJECTIVES: To evaluate the demographics, clinical aspects, and major organ involvement of patients with late-onset Behçet's syndrome (BS) in a tertiary center in China. METHODS: We conducted a cross-sectional study of consecutive BS patients in Huadong Hospital of Fudan University from September 2012 to January 2020. We compared clinical variables between patients with disease onset before and after 40 years of age. The relative risks (RRs) of clinical variables were calculated between the two age groups. Moreover, a hierarchical cluster analysis was conducted according to 29 variables to determine homogeneous subgroups in patients with late-onset BS. RESULTS: We enrolled 152 late-onset BS patients, with a median age at onset of 47 years (interquartile range, IQR: 43-52 years). There is a higher prevalence of intestinal ulcers in late-onset BS than in early-onset BS (RR 1.47), but a lower prevalence of ocular involvements (RR 0.54) and folliculitis (RR 0.46). Female sex was associated with genital ulcers, erythema nodosum, and arthritis. Four clusters (C1-C4) were formed. C1 (n = 71), the largest cluster, was defined as the mucocutaneous group, C2 (n = 20) as the arthritis group, C3 (n = 39) as the gastrointestinal group, in which all patients presented with intestinal lesions, and five cases with esophageal ulcers. In C4 (n = 22), showing a mixture of uveitis and vascular lesions, 15 patients presented with uveitis and 8 had vascular lesions, and 1 case had central nervous system lesions. CONCLUSION: Four phenotype clusters were identified. Patients with skin lesions comprised the largest cluster, while gastrointestinal, panuveitis, and cardiovascular clusters are the most commonly involved organs in late-onset BS patients. Key Points • Our analysis demonstrated the phenotype discrepancy between early and late onset groups. • Four phenotype clusters were identified, with gastrointestinal, panuveitis and cardiovascular clusters representing commonly involved organs.

Cluster analysis of phenotypes of patients with Behçet's syndrome: a large cohort study from a referral center in China.

INTRODUCTION: Behcet's syndrome (BS) is a complex, heterogeneous disorder. However, classification of its subgroups is still debated. The purpose of this study was to investigate the clinical features and aggregation of patients with BS in China, based on manifestations and organ involvements. METHODS: This was a cross-sectional study of BS patients in Huadong Hospital of Fudan University between September 2012 and January 2020. We calculated relative risks (RRs) of clinical variables according to sex. Moreover, we conducted a hierarchical cluster analysis applied according to eighteen variables to determine subgroups of patients. RESULTS: A total of 860 BS patients were included. Male sex was associated with ocular involvement (RR 2.32, 95% CI 1.67, 3.22, P < 0.0001), vascular involvement (RR 2.00, 95% CI 1.23, 3.23, P = 0.004), cardiac lesion (RR 5.46, 95% CI 2.33, 12.77, P < 0.0001), and central nervous system involvement (RR 2.95, 95% CI 1.07, 6.78, P = 0.007) and was negatively associated with genital ulcers (RR 0.84, 95% CI 0.79, 0.91, P < 0.0001). Five clusters (C1-C5) were observed. C1 (n = 307) showed the skin and mucosa type. In C2 (n = 124), all had articular involvement, barely having major organ involvement except for 18 cases with intestinal lesions. In C3 (n = 156), the gastrointestinal type, 144 patients presented with intestinal involvement, and 36 patients with esophageal ulcers. In C4 (n = 142), all subjects presented with uveitis. C5 (n = 131) consisted of 44 patients with cardiac lesions, 58 with vascular involvement, and 26 cases having central nervous system involvement. CONCLUSION: Our analysis confirmed sex differences in phenotypes of BS. Cluster analysis identified gastrointestinal, uveitis, and cardiovascular involvement cluster separately in different subsets, which represents the most commonly involved organs. Further research is required to replicate and clarify the patterns of phenotype in BS.

Risk factors of disease activity in patients with Behçet's syndrome.

OBJECTIVES: To investigate the clinical characteristics and laboratory data in Behçet's syndrome (BS) patients in China and analyze the risk factors of disease activity. METHOD: A retrospective analysis method was used and the demographic data and laboratory results were collected from 174 BS patients. Univariate and multivariate logistic regression analyses were used to analyze the demographic data and laboratory indexes whether that are risk factors or not of disease activity. RESULTS: The most common clinical manifestations of BS patients enrolled were mouth ulceration (48.85%), followed by erythema nodosum (20.69%), and eye involvement (13.75%), while the least common was headache (0%). Most active BS patients (96.55%) used 2 or ≥ 3 immunosuppressants to control disease, while most inactive patients (75%) used 0 or 1 immunosuppressant. The associated risk factors of disease activity consisted of disease duration, neutrophil-to-lymphocyte ratio (NLR), white blood cells, red blood cells, hemoglobin, platelets, fibrin degradation products, IgG, IgM, complement 3, complement 4, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), albumin, albumin-to-globulin ratio (AGR), and high-density lipoprotein (HDL) (P < 0.05 or P = 0.00). Disease duration (≤ 60 months) (OR 8.49, 95% CI 2.09-34.49, P = 0.003), NLR (≥ 2) (OR 8.68, 95% CI 2.12-35.49, P = 0.003), CRP (≥ 10 mg/L) (OR 41.12, 95% CI 8.43-200.70, P = 0.000), ESR (≥ 20 mm/H) (OR 9.60, 95% CI 2.41-38.18, P = 0.001), and AGR (< 1.5) (OR 12.42, 95% CI 2.92-52.80, P = 0.001) were the independent risk factors of disease activity in BS patients. CONCLUSIONS: Attention should be paid to the risk factors of disease activity and the medicine should be adjusted correspondingly. Key Points • The current diagnosis and efficacy evaluation of Behçet's syndrome (BS) mainly relied on clinical symptoms, while there are no specific laboratory biomarkers for reference. • In this study, we found that disease duration (≤ 60 months), neutrophil-to-lymphocyte ratio (≥ 2), C-reactive protein (≥ 10 mg/L), erythrocyte sedimentation rate (≥ 20 mm/H), and albumin-to-globulin ratio (< 1.5) were the independent risk factors of disease activity in BS patients. • In the ROC curve analysis, we found that erythrocyte sedimentation rate, C-reactive protein, and neutrophil-to-lymphocyte ratio could predict whether BS patients were active.