Factors influencing the recurrence of arterial involvement after surgical repair in Behçet disease.

OBJECTIVE: Arterial involvement in Behçet disease (BD) is rare, and its surgical management is a major concern because of its high recurrence rate. This study evaluated the influence of the surgical technique, device, and immunosuppressive treatment used on the postoperative recurrence in patients with non-pulmonary arterial BD. METHODS: A single-center, retrospective study was conducted of 23 patients meeting the international criteria for BD who underwent surgery for arterial involvement between May 1996 and September 2015. Recurrence was defined as the occurrence of arterial aneurysm or thrombosis during follow-up. Perioperative medical treatment and surgical technique used were reported. RESULTS: There were 47 surgical procedures performed in 23 patients. Mean follow-up was 8.4 ± 7.5 years. Initial arterial lesions were aneurysms and thrombosis in 85% and 15% of cases, respectively. Arterial lesions were aortic and peripheral in 48% and 52% of cases. Recurrence rate was 51%. Recurrences developed within <1 year in 24% of cases and at the same anatomic site in 92% of cases. Among the 24 recurrences, 17 were false aneurysms, 6 were thrombosis, and 1 was a true aneurysm in a different arterial site. To treat the arterial lesion, direct anastomosis was performed in 6 cases; bypass using the saphenous vein, graft, or allograft was performed in 6, 27, and 5 cases, respectively; and stent graft was used in 3 cases. Vascular lesions involved the aorta in 19 cases and a peripheral artery in 28 cases. Preoperative medical treatments, including colchicine, steroids, and immunosuppressants, significantly decreased recurrence rate: 28% (7/25) vs 75% (15/20) in untreated patients (P = .002). The recurrence rate was 42.5% (17/40) in patients treated postoperatively vs 80% (4/5) in untreated patients. The nature of the device used (vein, prosthetic graft, allograft, stent graft, or direct anastomosis) did not change the risk of recurrence. When anastomoses were protected using the prosthetic sleeving technique, the recurrence rate was three times lower (P = .08). CONCLUSIONS: Relapse is a main concern after surgical repair of arterial BD. This study suggests the need for targeted perioperative medical management to reduce the risk of arterial recurrence in BD patients. To this end, a multidisciplinary approach is mandatory. The use of sleeve anastomosis is associated with a numerically lower risk of recurrence. However, further studies are needed to confirm this efficacy.

Association of Interleukin-23R Gene Polymorphisms with Behcet's Disease Susceptibility: A Meta-Analysis of Case-control Studies.

BACKGROUND: The pathological mechanisms associated with the occurrence and development of Behcet's disease (BD) are not yet known. Two large genome-wide association surveys revealed an association between interleukin (IL)-23R single nucleotide polymorphism and BD. This study aimed to investigate the association between IL-23R gene polymorphisms and BD susceptibility. METHODS: Comprehensive literature search was performed across four online databases - PubMed, Embase, Cochrane Library, and Web of science. The included studies had to be published before May 15, 2019. The Newcastle-Ottawa scale was used to assess the quality of every included study, and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using the allele model of inheritance to evaluate the potential associations between IL-23R gene polymorphisms and BD risk. RESULTS: In all, 12 case-control studies comprising 6,926 BD patients and 10,211 controls were identified and included in this meta-analysis, in which 5 loci of IL-23R gene polymorphisms were investigated. Of these 5 loci, 2 were found to be significantly associated with BD susceptibility: rs17375018 (G vs. A, OR = 1.50, 95% CI: 1.34-1.68, P < .00001) and rs924080 (T vs. C, OR = 1.36, 95% CI: 1.29-1.43, P < .00001). Only a systematic review was conducted for rs12119179, rs11209032, and rs12141431, owing to the lack of sufficient data. CONCLUSION: This meta-analysis indicated that rs17375018 (G/A) and rs924080 (T/C) were associated with BD susceptibility. However, association of the other IL-23R polymorphisms could not be estimated owing to the lack of studies. ABBREVIATIONS: BD: Behcet's disease; SNP: single nucleotide polymorphism; HLA: human leukocyte antigen; IL: interleukin; OR: odds ratio; CI: confidence interval; HWE: Hardy-Weinberg equilibrium; UK: United Kingdom; NOS: Newcastle-Ottawa scale; GWAS: genome-wide association study; TNF-α: tumor necrosis factor-α.

BehÒ«et's Disease, and the Role of TNF-α and TNF-α Blockers.

In this both narrative and systematic review, we explore the role of TNF-α in the immunopathogenesis of Behçet's disease (BD) and the effect of treatment with TNF-α blockers. BD is an auto-inflammatory disease, characterized by recurrent painful oral ulcerations. The pathogenesis of BD is not yet elucidated; it is assumed that TNF-α may play a key role. In the narrative review, we report an increased production of TNF-α, which may be stimulated via TLR-signaling, or triggered by increased levels of IL-1ß and IFN-γ. The abundance of TNF-α is found in both serum and in sites of inflammation. This increased presence of TNF-α stimulates T-cell development toward pro-inflammatory subsets, such as Th17 and Th22 cells. Treatment directed against the surplus of TNF-α is investigated in the systematic review, performed according to the PRISMA guideline. We searched the Pubmed and Cochrane database, including comparative studies only. After including 11 studies, we report a beneficial effect of treatment with TNF-α blockers on the various manifestations of BD. In conclusion, the pivotal role of TNF-α in the immunopathogenesis of BD is reflected in both the evidence of their pro-inflammatory effects in BD and in the evidence of the positive effect of treatment on the course of disease in BD.

Behçet Syndrome as a Construct

We still do not know the cause(s) of Behçet syndrome. Most probably several, separate disease mechanisms are involved. I, like some others, propose we call it not a disease but a syndrome, a construct with a list of strong and weak elements. I like to think that this frank admission of our ignorance of its cause(s) will be an important semantic stimulus for more meaningful research.

Efficacy of the anti-IL 17 secukinumab in refractory Behçet's syndrome: A preliminary study.

OBJECTIVE: To evaluate the efficacy and safety of secukinumab in Behçet's patients with active mucocutaneous and articular manifestations refractory to previous treatments. METHODS: We retrospectively evaluated 5 patients treated with the IL17-inhibitor secukinumab and diagnosed with Behçet according to ISG/ICBD criteria. All patients had active mucocutaneous and articular manifestations refractory to colchicine, conventional DMARDs and at least one anti-TNFα agent. Four patients received secukinumab in the dose of 150 mg/monthly since also fulfilling the criteria for ankylosing spondylitis, while the fifth patient received secukinumab 300 mg/monthly because she met psoriatic arthritis criteria. Achievement of response was based on the number of oral ulcers, BASDAI and ASDAS for articular involvement, and BDCAF for Behçet activity. Complete response was defined as: i) decrease ≥50% in the number of oral ulcers; ii) BASDAI index <4; iii) ASDAS index <1.4; iv) decrease of 50% or more in BDCAF index. RESULTS: The patient starting secukinumab 300 mg/month successfully achieved complete response within 3 months. Complete response was maintained during all 9-months follow-up. Among the 4 subjects starting secukinumab 150 mg/month, two achieved complete response at month 6, but one relapsed. This patient and the two who not achieved complete response at month 6 were switched to secukinumab 300 mg/month. Within 3 months from the dosage increase, all three subjects successfully (re)achieved complete response. CONCLUSION: Our study suggested for the first time that secukinumab (either 150 mg and 300 mg/month) improved active mucocutaneous manifestations refractory to previous treatments, while secukinumab 300 mg/monthly resulted superior in inducing articular and complete response in Behçet's patients.

HLA Class I in Egyptian patients with Behçet's disease: new association with susceptibility, protection, presentation and severity of manifestations.

INTRODUCTION: Behçet's disease is an autoimmune disease with diverse clinical manifestations with vasculitis being the hallmark of the disease. The aim of this work is to study the genetic association between human leukocyte antigen (HLA) class-I molecules of Egyptians with Behçet's disease and the disease susceptibility and clinical patterns. METHODS: Fifty-seven patients diagnosed with Behçet's disease according to the 1990 International Study Group (ISG) criteria for Behçet's disease coming from Egyptian origin up to the third grandfather were included in the study. Healthy controls were taken from HLA Class-I case control studies in Egyptian population yielding a pool of 221 healthy controls. HLA Class-I typing for patients was done using Reverse Sequence specific oligonucleotide probes (rSSO). RESULTS: Male patients represented 89% of the sample. Mean age of onset was 25.81 (± 6.7) years and mean disease duration was 9.47 (± 7.4) years. Behçet's disease was associated with HLA-A*24 and HLA-B*42 (p = 0.001) and highly associated with HLA-A*68 and B*15 and B*51 (p < 0.001). While HLA A*03 and B*52 were protective for Behçet's (p = 0.002 and 0.007). Interestingly, HLA-B*51 and HLA-A*68 (p = 0.005 and 0.023) were associated with the blinding eye disease. HLA-B*51 was protective from Neurological and vascular involvement (p = 0.005 and 0.032, respectively). CONCLUSION: Behçet's disease is associated with HLA Class-I A*24, A*68 and B*15, B*42 and B*51 in Egyptian patients while A*03 and B*52 were found to be protective. Interestingly, HLA B*51 and A*68 could be considered as poor prognostic factor for eye involvement.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 1: psoriatic arthritis, SAPHO syndrome, Still's disease, Behçet's disease.

The coincidence of skin and joint inflammation poses a challenge for both dermatologists and rheumatologists. Adequate management of such disorders requires that physicians of both specialties have sound knowledge of the other discipline. In case of suspected joint involvement, familiarity with the diagnostic options available to rheumatologists enables dermatologists to selectively refer their patients for a rheumatology consult. The objective of the present review is to familiarize the reader with the stepwise diagnostic workup performed by rheumatologists today, including laboratory tests, musculoskeletal ultrasound, X-ray studies, and magnetic resonance imaging. Subsequently, we will discuss a number of disorders characterized by the concurrence of skin and joint inflammation, highlighting aspects of epidemiology, etiology and pathogenesis, clinical presentation, diagnosis and treatment. These disorders include psoriatic arthritis as well as autoinflammatory disorders such as SAPHO syndrome, Still's disease and Behçet's disease.

Behcet's Disease.

Behcet's disease is a rare systemic vasculitis disorder of unknown etiology characterized by recurrent attacks of acute inflammation affecting multiple parts of the body.

Is Behçet's disease a 'class 1-opathy'? The role of HLA-B*51 in the pathogenesis of Behçet's disease.

The association between carriage of the human leucocyte antigen (HLA)-B*51 allele and development of Behçet's disease (BD) has been known since the early 1970s, but the exact mechanisms responsible for its role in pathogenesis remain much-debated. In an effort to explain the disease process, it has been suggested that BD constitutes one of a newly termed group of diseases, the 'MHC-I-opathies'. Other MHC-I-opathies include ankylosing spondylitis and HLA-B*27-associated spondyloarthropathies and HLA-C*0602-associated skin psoriasis. Recent work analysing the peptidome of HLA-B*51 suggests that altered peptide presentation by HLA-B*51 is vital to the disease process. In this review, we argue that immune receptor interactions with HLA-B*51 or the HLA-B*51-peptide complex could lead to development of inflammation in BD. The evidence for CD8+ T cell involvement is weak, and based on emerging studies it seems more likely that natural killer (NK) or other cell interactions, perhaps mediated by leucocyte immunoglobulin-like receptor (LILR) or killer immunoglobulin-like receptor (KIR) receptors, are culpable in pathogenesis. HLA misfolding leading directly to inflammation is another hypothesis for BD pathogenesis that deserves greater investigation. Ultimately, greater understanding of HLA-B*51's unique role in BD will probably lead to improved development of therapeutic strategies.

Neutrophilic dermatoses: Pathogenesis, Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet disease.

Neutrophilic dermatoses are a heterogeneous group of inflammatory skin disorders that present with unique clinical features but are unified by the presence of a sterile, predominantly neutrophilic infiltrate on histopathology. The morphology of cutaneous lesions associated with these disorders is heterogeneous, which renders diagnosis challenging. Moreover, a thorough evaluation is required to exclude diseases that mimic these disorders and to diagnose potential associated infectious, inflammatory, and neoplastic processes. While some neutrophilic dermatoses may resolve spontaneously, most require treatment to achieve remission. Delays in diagnosis and treatment can lead to significant patient morbidity and even mortality. Therapeutic modalities range from systemic corticosteroids to novel biologic agents, and the treatment literature is rapidly expanding. The first article in this continuing medical education series explores the pathogenesis of neutrophilic dermatoses and reviews the epidemiology, clinical and histopathologic features, diagnosis, and management of Sweet syndrome, neutrophilic eccrine hidradenitis, and Behçet disease.

Recurrent oral ulcerations following heart transplant in a pediatric patient: A diagnostic dilemma.

Oral ulceration is a non-specific clinical finding with many potential causes. The persistence of oral ulcers in the context of a patient post-SOT is concerning for PTLD. There is growing evidence that SOT recipients may also be at higher risk of autoimmune diseases. This case report describes a pediatric patient with persistent oral ulcers after heart transplant, who underwent an extensive workup for PTLD, including repeat investigations, with a subsequent diagnosis of Behçet's disease.

Behçet Disease: New Developments in the Etiopathogenesis of an Old Silk Road Disease.

Behçet disease (BD) is a systemic inflammatory disorder that affects the skin, mucosa, eyes, joints, blood vessels, brain, and gastrointestinal tract. The etiopathogenesis of BD has not yet been fully elucidated, but disorganized immune responses against the stimuli of environmental triggering factors have been considered to play a major role in the pathogenesis of the disease in individuals with genetic susceptibility. Human leukocyte antigen (HLA)-B*51 is known to be the main factor involved in genetic susceptibility to BD. Among the environmental factors, infectious agents in particular are thought to be important. Immunological abnormalities could thus be the cornerstone in the development of BD. Along with cytokines that play a role in disease pathogenesis, numerous other cytokines have been recently identified or have been the focus of recent studies. This contribution sheds light on the etiopathogenesis and immunology of BD in relation to the current literature.

Dual effects of testosterone in Behcet's disease: implications for a role in disease pathogenesis.

Behcet's disease (BD) exhibits more severe disease course and higher mortality among male patients. However, underlying mechanisms of gender differences in clinical manifestations and disease severity are unclear. The aim of this study was to determine whether testosterone (T) has any role on BD pathogenesis. We studied peripheral blood mononuclear cells (PBMC) and neutrophils of BD patients and controls. Functional assay of neutrophils, cytokine measurements of culture supernatants and gene expressions on both cells were analyzed before and after T incubation. Neutrophils were significantly activated after incubation with T in only BD patients. Incubation with T caused significantly elevated interleukin (IL)-12 and IL-2 in BD. Gene expression of IL-10 was significantly downregulated after incubation with T in BD, especially in male patients. The same difference was observed in IL-10 levels in culture supernatant after T. Baseline TLR4 expression was significantly higher in BD patients compared to healthy donors (HC). Toll-like receptor (TLR) 4 expression on PBMC was significantly elevated in female BD patients. ERAP1 expressions of all patients and controls were decreased under the T effect but it differed significantly between BD vs HC. Baseline IL23R expression was higher in BD males compared with females but the difference disappeared after T. When BD patients were analyzed separately, baseline C-C motif chemokine receptor1 (CCR1), STAT4, TLR4 and KLRC4 expressions were lower in males. Despite immunosuppressive behavior in healthy subjects, T causes neutrophil hyperactivation and TH1 type immune alterations in BD patients. Our results suggest that T may have a role in BD pathogenesis by altering the expression level of IL-10, TLR4, ERAP1, CCR1.

Mucosal Lesions in an Allergy Practice.

The diagnosis and treatment of mucosal disease with an allergic pathogenesis are challenging. Oral allergy is often a hypersensitivity reaction with variable symptoms and physical exam findings. Clinical diagnosis requires a history of prior allergen exposure, a delay from exposure to clinical findings, and improvement following allergen removal. The past decades have seen great contributions to the field of oral allergy. The aim of this review is to provide an approach to the diagnosis and treatment of oral dermatologic disease with a focus on diseases with an investigated allergic pathogenesis.

Clinical relevance of midline fluid percussion brain injury: Acute deficits, chronic morbidities and the utility of biomarkers.

BACKGROUND: After 30 years of characterisation and implementation, fluid percussion injury (FPI) is firmly recognised as one of the best-characterised reproducible and clinically relevant models of TBI, encompassing concussion through diffuse axonal injury (DAI). Depending on the specific injury parameters (e.g. injury site, mechanical force), FPI can model diffuse TBI with or without a focal component and may be designated as mild-to-severe according to the chosen mechanical forces and resulting acute neurological responses. Among FPI models, midline FPI may best represent clinical diffuse TBI, because of the acute behavioural deficits, the transition to late-onset behavioural morbidities and the absence of gross histopathology. REVIEW: The goal here was to review acute and chronic physiological and behavioural deficits and morbidities associated with diffuse TBI induced by midline FPI. In the absence of neurodegenerative sequelae associated with focal injury, there is a need for biomarkers in the diagnostic, prognostic, predictive and therapeutic approaches to evaluate outcomes from TBI. CONCLUSIONS: The current literature suggests that midline FPI offers a clinically-relevant, validated model of diffuse TBI to investigators wishing to evaluate novel therapeutic strategies in the treatment of TBI and the utility of biomarkers in the delivery of healthcare to patients with brain injury.

[Behcet's disease and infection].

Behcet's disease (BD) is a systemic vasculitis of unknown etiology. Uveitis, which is common and therapeutically challenging, is the major ocular manifestation of BD. Researches have shown that, in addition to the genetic components (e.g. HLA-B51), environmental factors such as infection also play important roles in the pathogenesis of BD. In recent years, with the advances in bio-detecting technologies, accumulating evidence has shown an association between microbial infections and previously believed non-infectious immune disorders. Specifically, there has been increasing research interest in roles of infection in pathogenesis of BD. A variety of microbes, including streptococcus sanguis, staphylococcus aureus, intestinal flora, herpes simplex virus and etc., have been suggested to be involved. The objective of this article is to review current research progress concerning BD and infection, as well as to provide some recommendations for future investigations into this subject. (Chin J Ophthalmol, 2016, 52: 636-640).

A Single Nucleotide Polymorphism in the FOXP3 Gene Associated with Behçet's Disease in an Iranian Population.

UNLABELLED: Background: Behçet's Disease (BD) is a rare autoimmune disease that involves the dysfunction of regulatory T cells. FOXP3 is a key transcription factor in the development and function of T(reg) cells. Recent studies have shown SNPs in the FOXP3 contribute to the susceptibility to some autoimmune disorders. METHODS: To clarify the association between the FOXP3 gene and the risk of BD, 50 patients diagnosed with BD and 50 healthy controls from north-western Iran were genotyped by PCR-RFLP (Mun I and Pst I) for two SNPs including rs3761547 (-3499T/C) and rs3761548 (-3279 C/A) in the promoter region of the FOXP3 gene. In addition, a 506 bp nucleotide sequence of FOXP3 promoter was analyzed. RESULTS: The allele -3279 C/A was significantly associated with BD [p = 0.002; odds ratio (OR) = 3.841; 95% confidence interval (CI) 1.610 - 9.161]; whereas, there was no contribution of the FOXP3 polymorphism -3499T/C to BD [(p = 0.084); (OR = 0.348, 95% CI = 0.101 - 1.195)]. Meanwhile, sequence analysis showed 100% similarity in both controls and BD patient groups. CONCLUSIONS: Therefore, the SNP rs3761548 in the FOXP3 gene appears to contribute to the risk of Behçet's disease among the north-western Iranian population.

Clinical Features of Intestinal Behçet's Disease Associated with Myelodysplastic Syndrome and Trisomy 8.

Several studies have identified a relationship between myelodysplastic syndrome and Behçet's disease (BD), especially intestinal BD, and trisomy 8 appears to play an important role in these disorders. Despite this, only few case reports or series have been reported in gastroenterology, meaning that endoscopic findings and characteristics of intestinal BD have not been clarified yet. In this report, we describe three cases of intestinal BD associated with myelodysplastic syndrome and trisomy 8, and discuss the clinical features and problems of these disorders from a gastroenterology perspective.

Should we keep changing the diagnostic criteria for Behçet's disease?

In medicine, clinical acumen is used to achieve diagnosis, guide management and prevent disease. While for some diseases, diagnosis is reached with the assistance of objective tests, many conditions rely upon the use of clinical diagnostic criteria; Behçet's disease is one such case. In order to remain clinically relevant, as knowledge of a condition changes over time so too must its diagnostic criteria. Preferably, when new criteria for a disease are conceptualised it is through sound methodology, followed by a confirmation of accuracy by way of systematic validation and response to treatment. The most recently proposed revised International Criteria for Behçet's Disease for the diagnosis of Behçet's disease have been systematically validated and should replace the use of the clinically inferior International Study Group criteria, while not displacing the role of clinical judgement. Effort should now be invested in acquiring better understanding of the pathogenesis of the disease in the hope of developing a more objective test.