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 and pathological spectrum of aortitis in a Chinese cohort.

BACKGROUND: This study aimed to explore the clinical and pathological features of aortitis in China, which is a rare disease that is often overlooked preoperatively. METHODS: We reviewed the records of 2950 patients who underwent aortic surgery at Wuhan Asia General Hospital from 2016 to 2023. Clinical and pathological data were collected and compared across different groups. RESULTS: Out of 2950 patients, 15 had healed aortitis, 2 were healed Takayasu aortitis (TAK), and 13 were not further classified. Forty-two had active aortitis, including clinically isolated aortitis ([CIA], 42.9%), infectious aortitis ([IA], 26.2%), TAK (16.7%), and Behçet's syndrome ([BS], 14.3%), half of these cases were not recognized preoperatively. All patients who developed perivalvular leakage during follow-up had concurrent non-infectious valvulitis with mixed inflammatory pattern at the time of initial surgery. Seventeen out of 18 patients with CIA survived without complications, as did 8 out of 11 patients with IA, 6 out of 7 patients with TAK, and 2 out of 6 patients with BS. CONCLUSIONS: Half of the aortitis cases were initially diagnosed by pathologists. Noninfectious valvulitis with mixed inflammatory pattern is a risk factor for perivalvular leakage. BS is associated with a higher rate of complications. Patients with CIA have a good prognosis in China, which is different from the West.

Folliculitis might be associated with pathergy-positivity in patients with Behçet syndrome.

Pathergy test indicates nonspecific hyper-reactivity of the skin to aseptic trauma in Behçet syndrome (BS) and is considered as an adjunctive diagnostic test with a good specificity albeit with low sensitivity. We tested the hypothesis that a relationship exists between active clinical manifestations of BS and the pathergy-positivity when performed simultaneously. Pathergy test and detailed dermatologic examination were done in 105 BS patients (60M/45F); who were seen consecutively at the multi-disciplinary BS outpatient clinic in a single tertiary center. Information regarding demographic and clinical characteristics, pathergy test results at diagnosis, and details about treatment were obtained from patient charts. Disease activity was assessed using Behçet Disease Current Activity Form. Among 105 patients, 27 (25.7%) were pathergy-positive at the time of the study visit whereas 40.9% were pathergy-positive at the time of the diagnosis. There was no relation between pathergy test and patient age or disease duration, either. Pathergy-positivity was significantly more common in patients with folliculitis compared to those without folliculitis (40.7% vs 19.2%; P = .026). The test was also positive in all 3 patients with leg ulcers due to venous stasis. We found that among all skin-mucosa lesions only the presence of folliculitis was associated with pathergy positivity with statistical significance. It was also remarkable that the current pathergy was positive in all 3 patients with active leg ulcers but this finding warrants further studies because of the low patient numbers.

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.

Pathergy-like reaction induced by laser hair removal in a patient with Behçet disease.

Behçet disease (BD) is a rare systemic vasculitis of unknown etiology, primarily characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions. Pathergy test positivity is a nonspecific inflammatory response of the skin to trauma and supports the diagnosis. Recently, new inducers of pathergy reactions have been identified, for example, the placement of dental braces and laser hair removal. Our clinical case highlights the importance of thinking about this potential pathergy inducer in BD patients, to improve their quality of life and avoid complications.

Clinical, Endoscopic, and Histopathologic Gastrointestinal Disease in an American Cohort With Behçet's Disease.

INTRODUCTION: Behçet's disease (BD) is a chronic systemic vasculitis characterized by oral and genital ulcers, uveitis, and skin lesions. Patients with BD may develop gastrointestinal (GI) disease; however, characterization of GI disease in American cohorts is lacking. In this article, we present clinical, endoscopic, and histopathologic GI findings in an American cohort of patients with BD. METHODS: Patients with established BD were evaluated prospectively at the National Institutes of Health. Demographic and clinical data were collected including BD manifestations and GI symptoms. Endoscopy with histopathologic sampling was performed for both clinical and research indications with written consent. RESULTS: Eighty-three patients were evaluated. The majority were female (83.1%) and white (75.9%). Mean age was 36 ± 14.8 years. GI symptoms were reported in 75% of cohort with nearly half of reporting abdominal pain (48.2%) and significant numbers reporting acid reflux, diarrhea, and nausea/vomiting. Esophagogastroduodenoscopy was performed in 37 patients; erythema and ulcers were the most common found abnormalities. Colonoscopy was performed in 32 patients with abnormalities including polyps, erythema, and ulcers. Endoscopy was normal in 27% of esophagogastroduodenoscopies and 47% of colonoscopies. Vascular congestion was demonstrated on the majority of random biopsies throughout the GI tract. Inflammation was not highly prevalent on random biopsies except in the stomach. Wireless capsule endoscopy was performed on 18 patients; ulcers and strictures were the most common abnormalities. DISCUSSION: GI symptoms were common in this cohort of American patients with BD. Endoscopic examination was often normal; however, histopathologic examination demonstrated vascular congestion throughout the GI tract.

Chemokines and chemokine receptors in Behçet's disease.

Behçet's disease (BD), a chronic vascular inflammatory disease, is characterized by the symptoms of ocular lesions, recurrent genital and oral ulcers, skin symptoms and arthritis in addition to neurological, intestinal and vascular involvement. The pathogenesis of BD is poorly understood, and there are no effective laboratory markers for the diagnosis of BD. In addition, BD is presently incurable. Chemokines, a family of small secreted chemotactic cytokines, interact with chemokine receptors and mediate the migration, localization and cellular interactions of inflammatory cells. Several studies have suggested that chemokines and their receptors play an important role in the occurrence and development of BD and that these chemokines along with their receptors can be utilized as biomarkers and therapeutic targets. In the present review, chemokines and chemokine receptors involved in BD and their potential application in diagnosis and therapy have been discussed.

Association between Serum α-Klotho Levels and Behçet Disease.

BACKGROUND: Endothelial dysfunction (ED) has a well-known role in promoting vascular inflammation in Behçet disease (BD). α-klotho is involved in regulation of endothelial function, and its reduction has been reported to be associated with ED. OBJECTIVE: To assess serum α-klotho in patients with BD, compared with healthy control individuals. METHODS: In a cross-sectional study, 55 patients with BD and 30 age- and sex-matched healthy controls were enrolled, and their serum levels of α-klotho were measured. RESULTS: Common clinical symptoms in patients with BD were oral aphthous ulcers, uveitis, and genital ulcers. Median (IQR) serum α-klotho levels in the BD and control groups were 0.30 (0.20-0.70) and 1.00 (0.70-2.52) ng/mL, respectively. The difference was statistically significant (P = .005). No significant correlation was observed between serum α-klotho and age (r = 0.194; P = .14). Serum α-klotho levels in patients with uveitis were significantly lower. CONCLUSION: α-klotho may have a role in the pathogenesis of ED and is a potential biomarker for uveitis in BD.

Behcet's Disease Mimicking Crohn's Disease: A Diagnostic Pitfall in GI Tract Biopsies.

Behcet's disease is a rare entity. It's a multi-systemic inflammatory disease of unknown etiology characterized by recurrent ulcers and vasculitis, mainly including the oral cavity, eyes, gastrointestinal tract and joints. Crohn's disease is a chronic inflammatory disorder that may affect the same organs as Behcet's disease, however more frequently the gastrointestinal tract. Distinguishing Behcet's disease from Crohn's disease can be challenging due to the overlapping clinical presentation and similar morphology features on pathology biopsy specimens. This is a case report of a 32-year-old female who first presented at the emergency department with fatigue, weight loss, arthralgia, and erythema nodosum. The patient was admitted for oral ulcers, skin rash, genital ulcers, and melena one month later. Treatment with prednisone was started at the time and further workup for Behcet's disease versus inflammatory bowel disease was started. Her esophagus biopsy shows granulomatous-like vasculitis, and her colon biopsies show overlapping features with Crohn's disease. Herein, we present a rare and interesting case in which Behcet's disease mimics inflammatory bowel disease on the gastrointestinal tract biopsies but with some unique findings and diagnostic pitfalls for gastrointestinal tract vasculitis and ulceration.

Myeloid sarcoma arising at the uterine cervix in a patient with intestinal Behçet's disease and concurrent myelodysplastic syndrome: A case report.

INTRODUCTION: Myeloid sarcoma (MS) is an extramedullary tumor that consists of myeloblasts and rarely involves the female reproductive organs. Intestinal Behçet's disease (BD) is a chronic, inflammatory illness that is often associated with myelodysplastic syndrome (MDS). When MDS is diagnosed, some patients with intestinal BD experience synchronous gastrointestinal flares. CASE PRESENTATION: We report the case of a 49-year-old woman who presented with vaginal bleeding and an incidentally identified MS in the uterine cervix. Subsequent bone marrow biopsy showed simultaneous MDS without chromosomal abnormalities. This is the first reported case of concomitant MS, myelodysplastic disease, and intestinal BD. CONCLUSIONS: The accurate diagnosis of MSs that develop at non-predominant sites is crucial for a positive patient prognosis. MDS should be suspected in patients with a history of intestinal BD diagnosed with MS.

Macrophage polarization toward M1 phenotype through NF-κB signaling in patients with Behçet's disease.

BACKGROUND: Macrophages are key innate immune cells implicated in the pathogenesis of Behçet's disease (BD), and macrophage polarization plays a pivotal role in inflammatory response. This study aimed to investigate the role of BD serum on the phenotypes and functions of macrophage polarization. METHODS: BD or HC serum-treated human monocyte-derived macrophages (HMDMs) were examined M1/M2 phenotypes using flow cytometry and ELISA. The phagocytic capacity of HMDMs and CD4+T cell differentiation facilitated by HMDMs were measured by flow cytometry. Transcriptome analysis of BD and HC serum-stimulated HMDMs was conducted to identify differentially expressed genes. NF-κB signaling was examined using western blot to explore the mechanism of macrophage polarization induced by BD serum. RESULTS: BD serum-treated macrophages expressed a higher level of CD86, IL-12, and TNF-α and a lower level of CD163, which were compatible with the M1-like phenotype. Furthermore, BD serum-treated macrophages showed enhanced phagocytic capacity and promoted more Th1 cell differentiation. Sixty-one differentially expressed genes were identified between BD and HC serum-treated macrophages and were enriched in NF-κB signaling. BD serum-treated macrophages showed upregulated p-p65 and downregulated IκBα, and NF-κB inhibitor attenuated BD serum-stimulated M1-like phenotype. CONCLUSIONS: BD serum promoted macrophage polarization toward a proinflammatory M1-like phenotype through NF-κB signaling and potentially facilitated inflammation in BD. M1 polarized macrophages may be a potential therapeutic target for BD.

Ruptured innominate artery pseudoaneurysm presenting as hoarseness in Behçet's syndrome: a case report.

BACKGROUND: Vascular involvement is an infrequent clinical manifestation of Behçet's syndrome. Owing to the rarity of arterial involvement in Behçet's syndrome, there is limited experience in managing this phenomenon. CASE PRESENTATION: Here, we report a 28-year-old Iranian man with a Behçet's syndrome background, who presented with shoulder pain and hoarseness. Chest computed tomography angiography was conducted with a suspicion of a vascular pathology causing pressure on the recurrent laryngeal nerves. The patient was diagnosed with a ruptured innominate artery pseudoaneurysm. An innominate artery to the right common carotid artery bypass was performed, and the pseudoaneurysm was excised and replaced with an expandable polytetrafluoroethylene graft. Eventually, the patient was discharged after an uneventful hospital course. CONCLUSION: It appears that we are still a long way from finding the optimal treatment for Behçet's syndrome vascular involvement, and a combination of surgical and medicinal treatments is required.

Behçet's disease with intestinal involvement: case-based review.

Behçet's disease (BD) is a rare (especially in East Europe, Ukraine) systemic vasculitis of blood vessels of varying calibers throughout the body that affects various organs. The variability of the clinical features requires the involvement of doctors of different specialties in the management of such patients. The work was aimed to conduct a literature review of the intestine involvement and skin lesions in BD based on the clinical case with bloody diarrhea at the onset, and to assess the frequency of development of various clinical syndromes in intestinal BD. This is an attempt at describing a manifestation of BD with colitis and to emphasize the necessary revision of BD diagnostic criteria with special attention to early manifestations of BD with gastrointestinal tract involvement.

SMALL BOWEL IS LARGELY AFFECTED IN BEHÇET'S DISEASE: A LONG-TERM FOLLOW-UP OF GASTROINTESTINAL SYMPTOMS.

BACKGROUND: Behçet's disease is a rare immune-mediated disorder that can affect the gastrointestinal tract. The prevalence and extension of small bowel involvement is largely unknown. OBJECTIVE: The aim of this study was to describe the small bowel lesions diagnosed by double-balloon enteroscopy (DBE) and to verify if these findings were associated to the presence of gastrointestinal symptoms and disease activity after long-term follow-up. METHODS: This study included 19 Behçet's disease patients who underwent DBE. After a mean follow-up of 15 years the endoscopic findings were associated to the presence of gastrointestinal symptoms, disease activity and current therapy through collection of electronic medical records. RESULTS: A total of 63.2% patients were female and the mean age was 37 years at the time of DBE. Mean disease duration at baseline was 24 years. 11 patients had no gastrointestinal symptoms and eight patients presented either abdominal pain, gastrointestinal bleeding or diarrhea. The average procedure time was 1 hour and 30 minutes and the ileum was achieved in all patients but one. Small bowel ulcers were diagnosed in 78.9%, with 63.1% of jejunal involvement. Two patients presented only small bowel edema and two were normal by DBE. Eight patients had concomitant gastric ulcers. Gastrointestinal symptoms prior to DBE were present in 36.8% of the patients and, after follow-up, all of them persisted with some of the symptoms. Bleeding was reported by three patients at baseline and persisted in only one patient. The frequency of treatment with steroids and immunomodulators was 31.6% and 57.9% at baseline, respectively, and 21% in both at the end of the follow-up. No patient was treated with biologics at the time of the DBE procedure and the current rate of biologic use is 21%. CONCLUSION: Small bowel involvement in Behçet's disease was frequently demonstrated by DBE even in asymptomatic patients. Understanding clinical evolution of the disease over the years and the impact of such diagnosis still represents a challenge, possibly with the need for novel treatment.

The Immunogenetics of Behcet's Disease.

Behcet's disease (BD) is an autoimmune disorder that affects the blood vessels and thus could entangle virtually every organ of the body. Oral ulceration, genital aphthous lesions, and ocular inflammation are the main manifestations of the disease that tend to have a chronic, relapsing-remitting course. The disease comes from an association between environmental and genetic backgrounds. The clustering of cases in families and the high rate of co-occurrence of the disease in siblings were the initial findings that proposed a genetic basis for BD. Later on, multiple case-control studies and genome-wide association studies were able to clarify particular genes included in the etiopathogenesis of BD. The major gene polymorphisms include HLA and HLA-related genes, interleukins, and other genes involved in inflammation and transcription activation. Herein we have summarized the susceptibility genes that are associated with BD. Investigations on the genetics of BD could potentially clarify the disease pathogenesis and provide insights for the development of better treatments.

Efficacy and predictor of anti-TNFα agents in patients with intestinal Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a recurrent multisystem inflammatory disease. Anti-tumor necrosis factor (TNF) α agents have been used to treat patients with intestinal BD with severe disease activity or those who are resistant to conventional treatments; however, the long-term efficacy of anti-TNFα agents in intestinal BD remains unclear. In the present study, we investigated the clinical outcomes and predictors of discontinuation of anti-TNFα agents in patients with intestinal BD. METHODS: We reviewed the medical records of patients with intestinal BD who received first-line anti-TNFα agents between January 2009 and June 2020. The primary outcome was the percentage of patients who continued anti-TNFα therapy for 48 weeks. Secondary outcomes included the percentage of patients who achieved marked improvement, complete remission, and mucosal healing, as well as predictors of discontinuation of anti-TNFα agents. RESULTS: A total of 29 patients were included in the study. Twenty-two (75.9%) patients continued anti-TNFα therapy for 48 weeks. The percentage of patients who achieved marked improvement, complete remission, and mucosal healing at week 48 was 48.3%, 37.9%, and 48.3%, respectively. At week 96, 11 (37.9%) patients achieved marked improvement, complete remission, and mucosal healing. A higher C-reactive protein level (CRP; ≥ 1 mg/dL) at baseline was a predictor of discontinuation of anti-TNFα agents. CONCLUSIONS: The 48-week continuation rate of anti-TNFα agents was 75.9% in bio-naïve patients with intestinal BD. However, a higher baseline CRP level (≥ 1 mg/dL) was associated with discontinuation of anti-TNFα agents.

Retinal microvasculature features in patients with Behcet's disease: a systematic review and meta-analysis.

This meta-analysis aimed to analyze retinal microvasculature features in eyes with Behçet's disease (BD) using optical coherence tomography angiography (OCTA). Electronic databases, including PubMed, Web of Science, Embase, and Cochrane Library, were comprehensively searched for published studies comparing retinal microvasculature characteristics between eyes with BD and controls. Continuous variables were calculated using the mean difference (MD) with 95% confidence interval (CI). Review Manager software (version 5.30) was used to conduct statistical analysis. A total of 13 eligible studies involving 599 eyes with BD and 622 control eyes were included in the meta-analysis. The pooled results showed that the macular whole enface superficial and deep vessel density (VD) values measured by OCTA were significantly lower in eyes with BD than in control eyes (superficial VD: MD = - 3.05, P < 0.00001; deep VD: MD = - 4.05, P = 0.0004). The foveal superficial and deep VD values were also significantly lower in the BD group than in the control group (superficial VD: MD = - 1.50, P = 0.009; deep VD: MD = - 4.25, - = 0.03). Similarly, the analysis revealed a significant reduction in the parafoveal superficial and deep VD in eyes with BD than in control eyes (superficial VD: MD = - 3.68, P < 0.00001; deep VD: MD = - 4.95, P = 0.0007). In addition, the superficial and deep foveal avascular zones (FAZs) were significantly larger in patients with BD than in controls (superficial FAZ: MD = 0.06, P = 0.02; deep FAZ: MD = 0.12, P = 0.03). The present meta-analysis found that macular whole enface VD, foveal VD, and parafoveal VD were lower in eyes with BD, and the FAZ was larger in patients with BD. The findings suggest that OCTA can assist clinicians in diagnosing and monitoring the status of patients with BD.

The efficacy and safety of anti-tumor necrosis factor agents in the treatment of intestinal Behcet's disease, a systematic review and meta-analysis.

BACKGROUND AND AIM: Behcet's disease is a systemic vasculitis that can involve gastrointestinal tract. This is a systematic review and meta-analysis evaluating the efficacy and safety of anti-tumor necrosis factor (TNF) agents in treating patients with intestinal Behcet's disease. METHODS: We conducted searches on PubMed, Embase, and Cochrane. Data from eligible studies were used to calculate the pooled estimate of proportions of clinical remission, mucosal healing at Months 3, 6, 12, and 24 as well as the pooled incidence of adverse drug reactions. And subgroup analysis based on the specific type of anti-TNF agents was performed. RESULTS: Of the 828 studies initially identified, 13 were included finally, all of which were single-arm cohort studies. The pooled proportions of clinical remission at Months 3, 6, 12, and 24 were 0.61 (95%CI 0.48-0.78), 0.51 (95%CI 0.40-0.66), 0.57 (95%CI 0.48-0.67), and 0.38 (95%CI 0.16-0.88), respectively. The pooled proportions of mucosal healing at Months 3, 6, 12, and 24 were 0.66 (95%CI 0.50-0.86), 0.82 (95%CI 0.48-0.98), 0.65 (95%CI 0.51-0.81), and 0.69 (95%CI 0.39-1.00), respectively. The pooled estimate of proportion of overall adverse drug reactions for infliximab was 0.22 (95%CI 0.07-0.69). CONCLUSIONS: Anti-TNF agents, including infliximab and adalimumab, were an efficient therapy for intestinal Behcet's disease. The safety of anti-TNF agents used in the treatment of intestinal Behcet's disease was acceptable.