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.

Identification of hub genes and gene modules associated with Behçet's disease by weighted gene co-expression network analysis of neutrophil transcriptome.

OBJECTIVES: Behçet's disease (BD) is a chronic inflammatory condition with recurrent skin lesions, uveitis, and oral and genital ulcers. Neutrophils are important in the pathogenis of BD, but their molecular mechanisms are unclear. METHODS: We performed weighted gene co-expression network analysis on the transcriptome of neutrophils from 10 BD patients and 10 healthy controls to identify hub genes and gene modules associated with BD. RESULTS: We found eight co-expression modules with different biological functions. The turquoise module was involved in response to hydrogen peroxide and reactive oxygen species, the blue module was involved in response to external stimulus and inflammatory response, and the brown module was involved in the type I interferon signaling pathway. We further identified hub genes and transcription factors in each module by using module membership and gene significance. CONCLUSIONS: Our results reveal novel gene modules and hub genes that are associated with neutrophil activation and dysfunction in BD, which could serve as potential biomarkers and therapeutic targets for this disease.

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.

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.

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.

Clinical characteristics and factors influencing the prognosis of Behçet's disease complicated with vascular involvement.

Background: Vascular Behçet's disease (VBD) might involve all sizes of arterial and venous vessels. Major vascular involvement caused the primary death in Behçet's syndrome (BS). We aimed to investigate the clinical characteristics and factors influencing the prognosis of VBD. Patients and methods: A retrospective analysis of the prospectively collected data of the Shanghai BS database from October 2012 to October 2018 was conducted. Patients who were diagnosed with BS and merged with venous thrombosis, arterial aneurysms, and arterial stenosis/occlusions were enrolled. Results: There were 47 patients with vascular involvement among 836 BS patients, 38 males and 9 females. The numbers of patients with venous thrombosis, arterial aneurysm, and arterial stenosis/occlusion were 25 (53.2 %), 21 (44.7 %), and 12 (25.5 %), respectively. Nearly half of the venous thromboses were located in limbs (n = 22, 46.8 %). Arterial aneurysm was the main form of arterial lesion. Most of the patients (93.6 %) were treated with corticosteroids and immunosuppressants. Late onset of BS or with arterial involvement had lower treatment response. Therapy with biological agents had significantly better results than that in the group without biological treatment (94.1 % vs. 80 %, P = 0.005). Conclusions: VBD showed a male preponderance and more than half of the patients presented with venous thrombosis. Late onset and arterial involvement were associated with poor prognosis. Therapy with biological agents is a viable alternative treatment to improve the prognosis.

Serum uric acid could be served as an independent marker for increased risk and severity of ascending aortic dilatation in Behçet's disease patients.

OBJECTIVE: This study aimed to investigate the correlation of serum uric acid (SUA) with risk and dilatation diameter of ascending aortic dilatation (AAD) in Behçet's disease (BD) patients. METHODS: Seventeen BD patients complicated with AAD and 20 BD patients without AAD were consecutively enrolled and categorized into AAD group and control group, respectively. Ascending aortic dilatation was determined by two-dimensional doppler echocardiographic examination, and AAD was defined as a diameter of ascending aorta ≥3.8 and <4.4 cm. SUA was detected by quantitative immunoassay method. RESULTS: Ascending aortic dilatation patients presented with higher proportion of male patients (P = 0.003), hypertension occurrence (P = 0.036) and increased diameter of ascending aorta (P < 0.001) compared to controls. SUA was elevated in AAD patients compared to controls (P = 0.002), and receiver operating characteristic curve displayed that SUA presented with great predictive value for AAD risk in BD patients with area under curve (AUC) 0.821 (95% CI 0.675-0.966). Pearson's analysis also disclosed that SUA was positively correlated with ascending aortic diameter in total BD patients. However, no difference of CRP (P = 0.219) or ESR (P = 0.320) between AAD patients and controls was observed, and no correlation of CRP (R = -0.150, P = 0.377) or ESR (R = 0.067, P = 0.692) with ascending aortic diameter in total BD patients was discovered either. Further multivariate logistic regression illuminated that SUA was an independent factor predicting AAD risk in BD patients (P = 0.031). CONCLUSIONS: Serum uric acid could be served as an independent marker for increased risk and severity of AAD in BD patients.

Differentiation between intestinal Behçet's disease and Crohn'sdisease based on endoscopy

Background/aim: Differentiating intestinal Behçet's disease (BD) from Crohn's disease (CD) is highly challenging, as they often mimic each other in terms of clinical manifestations. Endoscopy is an important modality for distinguishing bowel lesions. The study was designed to identify clinical manifestations that are easily confused and to evaluate the efficacy of endoscopy for distinguishing intestinal BD from CD by several overlapping signs. Materials and methods: The data from 111 patients with intestinal BD and 81 patients with CD were retrospectively analyzed. Logistic regression was applied to establish a prediction model based on endoscopic findings for the differential diagnosis. The diagnostic efficacy of endoscopy was verified using the area under the receiver operating characteristic (ROC) curve. Results: Among intestinal BD patients mucocutaneous lesions were the leading clinical manifestations. Gastrointestinal symptoms were common in CD but were rare in intestinal BD (P < 0.001). CD patients with moderate-to-severe activity were more common than intestinal BD patients presenting with equivalent activity (P < 0.05). Independent factors that distinguished intestinal BD from CD were solitary ulcer in the ileocecal area (P < 0.001), perianal abscess (P = 0.049), single segment (P < 0.001), round intestinal ulcer (P = 0.013), intestinal obstruction (P = 0.035), and fistula (P < 0.001). The scores ranged from ­2 to 3. The area under the ROC curve was 0.874 (95% CI: 0.823­0.926) (P < 0.001). With a score of 1.5 as the diagnostic cutoff value, the sensitivity and specificity were 76.3% and 80.6%, respectively. Conclusion: Mucosal injuries were rarer in patients with intestinal BD than in those with CD. The differentiation model combining several endoscopy features appeared to be reliable for distinguishing between intestinal BD and CD.

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

BACKGROUND: Intestinal Behcet's disease (BD) is a specific subtype of BD. Effective drug therapy for intestinal BD remains elusive. AIMS: To investigate long-term outcomes and identify predictors of sustained response in intestinal BD patients receiving infliximab (IFX) treatment. METHODS: 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. RESULTS: Totally, 27 active intestinal BD patients were enrolled. Sustained responses were observed in 17 patients, after a median follow-up duration 24 months (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 6.85 mg/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. CONCLUSIONS: 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.

Interleukin-1-related genes polymorphisms in Turkish patients with Behçet disease: a meta-analysis.

OBJECTIVES: Polymorphisms in the Interleukin (IL)-1-related genes at the locations -889, -511, + 3962 and mspa1l 1100 have been investigated for possible association with Behçet's disease (BD). METHODS: A literature-based search was conducted to identify all relevant studies. Five independent studies from Turkish population met the included criteria. RESULTS: IL-1α -889 CT [odds ratio (OR) = 0.72, 95% confidence interval (CI) = 0.55-0.95], IL-1α -889 TT (OR = 0.61, 95% CI = 0.40-0.93), IL-1ß + 3962 C (OR = 1.41, 95% CI = 1.07-1.88), IL-1ß + 3962 T (OR = 0.71, 95% CI = 0.53-0.94) IL-1ß + 3962 CC (OR = 2.08, 95% CI = 1.08-3.99), IL-1ß + 3962 CT (OR = 0.58, 95% CI = 0.38-0.88), IL-1 receptor antagonist (IL-1 Ra) mspa1l 1100 CT (OR = 0.69, 95% CI = 0.49-0.96), IL-1 Ra mspa1l 1100 TT (OR = 1.50, 95% CI = 1.08-2.08) had a significant association with BD. The pooled estimates for IL-1α -889 C, IL-1α -889 CC, IL-1α -889 T had a non-significant association with BD. CONCLUSIONS: IL-1α -889 CT, IL-1α -889 TT, IL-1ß + 3962 C, IL-1ß + 3962 T, IL-1ß + 3962 CC, IL-1ß + 3962 CT, IL-1 Ra mspa1l 1100 CT, IL-1Ra mspa1l 1100 TT promoter polymorphisms may confer susceptibility to BD in Turkish population.

Intercellular adhesion molecule-1 polymorphisms in patients with Behçet disease: a meta-analysis.

OBJECTIVES: To examine the association between the Intercellular adhesion molecule-1 (ICAM1) Polymorphisms and Behçet's disease. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials for original studies up to July 31, 2012 were searched for relevant studies. All pooled odds ratios (ORs) were derived from either fixed or random-effects model with its 95% confidence intervals (CI). RESULTS: Five studies met the inclusion criteria. Overall, ICAM1 E469 (OR = 1.45, 95% CI = 1.06-1.97), genotype ICAM1 469 E/E (OR = 1.45, 95% CI = 1.09-1.94), ICAM1 241 G/R (OR = 3.65, 95% CI = 1.69-7.89), had significant associations with Behçet's disease. A significant association was found between the presence of skin lesions and genotype ICAM1 469 E/E (OR = 3.52, 95% CI = 1.62-7.66). CONCLUSIONS: Behçet's disease was associated with the ICAM1 E469, genotype ICAM1 469 E/E, ICAM1 241 G/R polymorphisms in different ethnic groups. Among patients, genotype ICAM1 469 E/E had a significant association with skin lesion.

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.

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.

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 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.

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.

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.

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.