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Background: Cyclophosphamide and infliximab are recommended as induction therapies for severe Behçet's syndrome. Whether infliximab is safer and more effective than cyclophosphamide in treating severe Behçet's syndrome is not known., Methods: In this phase 2, Bayesian, multicenter randomized controlled trial, we assigned patients fulfilling the International Study Group's criteria for Behçet's syndrome who had major vascular or central nervous system involvement to receive either intravenous infliximab (5 mg/kg at weeks 0, 2, 6, 12, and 18) or cyclophosphamide (0.7 g/m 2 intravenously at weeks 0, 4, 8, 12, 16, and 20, with a maximal dose of 1.2 g/infusion). All patients received the same glucocorticoid regimen. The primary outcome was complete response (clinical, biological, and radiological remission with a daily prednisone dose ≤0.1 mg/kg) at week 22., Results: Between May 2018 and April 2021, 52 patients with severe Behçet's syndrome (n=37 [71%] with vascular Behçet's syndrome and n=15 [29%] with neuro-Behçet's syndrome) were randomly assigned to receive either infliximab or cyclophosphamide. Complete response was achieved by 22 out of 27 (81%) and 14 out of 25 (56%) patients in the infliximab and cyclophosphamide treatment groups, respectively (estimated difference, 29.8 percentage points; 95% credible interval, 6.6 to 51.7). The posterior probability that at least 70% of treated individuals achieved complete response by week 22 was 97.4% for infliximab and 6.0% for cyclophosphamide. Overall, adverse events were recorded in 8 out of 27 (29.6%) patients receiving infliximab and 16 out of 25 (64%) patients receiving cyclophosphamide (estimated difference, -32.3 percentage points; 95% credible interval, -55.2 to -6.6). Serious adverse events were reported in 15% and 12% of patients receiving infliximab and cyclophosphamide, respectively., Conclusions: Among patients with severe Behçet's syndrome, induction therapy with infliximab had a superior complete response rate at 22 weeks and fewer adverse events than induction with cyclophosphamide. (Funded by the French Ministry of Health.).

Behcet disease (BD) is a systemic vasculitis which can involve many different organ systems. Neurological involvement (NBD) occurs in 5.3% to 59% of BD patients. The diagnosis is challenging especially in case of inaugural neurological presentation, and is based on a constellation of clinical, laboratory, and neuroimaging findings. NBD can be subdivided into parenchymal NBD through an immune mediated meningoencephalitis with a predilection to the brainstem, basal ganglia, thalamus, cranial nerves, and spinal cord involvement, and extraparenchymal NBD encompassing cerebral veinous thrombosis and intracranial arterial involvement. Brain magnetic resonance shows ill-defined areas of oedema with high signal intensity on T2-FLAIR images, isointense or hypointense in T1-weighted images in the basal ganglia area or in the brainstem, which may extend to the diencephalic structures. Swelling might be noticed. Hemorrhages can be seen, such as contrast enhancement (blood brain barrier disruption). Magnetic resonance venography and computerized tomographic angiography can be used to diagnose extraparenchymal NBD. Treatment of parenchymatous forms is based on glucocorticoids associated with oral immunosuppressants (azathioprine, mycophenolate mofetil or methotrexate) in mild forms, and intravenous cyclophosphamide or infliximab in severe forms. The management of cerebral thrombosis consists of steroids course associated with an oral anticoagulation. An early recognition of this condition is mandatory to initiate adequate therapies in order to improve outcomes and limit the risk of sequelae, relapses, or death. The aim of this review is to summarize a comprehensive review on the various neurological presentations of BD with emphasizes on diagnostic tools, prognosis, and therapeutic issues., (Copyright © 2024 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Objective: Behçet's disease (BD) is a systemic vasculitis with inflammatory lesions mediated by cytotoxic T cells and neutrophils. Apremilast, an orally available small-molecule drug that selectively inhibits phosphodiesterase 4 (PDE4), has been recently approved for the treatment of BD. We aimed to investigate the effect of PDE4 inhibition on neutrophil activation in BD., Methods: We studied surface markers and reactive oxygen species (ROS) production by flow cytometry, and neutrophil extracellular traps (NETs) production and molecular signature of neutrophils by transcriptome analysis before and after PDE4 inhibition., Results: Activation surface markers (CD64, CD66b, CD11b, and CD11c), ROS production, and NETosis were up-regulated in BD patient neutrophils compared to healthy donor neutrophils. Transcriptome analysis revealed 1,021 significantly dysregulated neutrophil genes between BD patients and healthy donors. Among dysregulated genes, we found a substantial enrichment for pathways linked to innate immunity, intracellular signaling, and chemotaxis in BD. Skin lesions of BD patients showed increased infiltration of neutrophils that colocalized with PDE4. Inhibition of PDE4 by apremilast strongly inhibited neutrophil surface activation markers as well as ROS production, NETosis, and genes and pathways related to innate immunity, intracellular signaling, and chemotaxis., Conclusion: We highlight key biologic effects of apremilast on neutrophils in BD., (© 2023 American College of Rheumatology.)

Background: Association of neutrophilic dermatosis (ND), hidradenitis suppurativa (HS) and Behçet's disease (BD) and shared efficacy of TNFα axis blockade suggests common physiopathology., Objectives: To investigate the clinical features and therapeutic response of ND and HS associated with BD., Methods: We identified 20 patients with ND or HS associated with BD among 1462 patients with BD., Results: We analysed 20 (1.4%) patients diagnosed with ND or HS associated with BD: 13 HS, 6 pyoderma gangrenosum (PG), and 1 SAPHO. Our 6 PG cases over 1462 BD patients accounts for 400/100 000 prevalence. Thirteen had bipolar aphthosis, 6 vascular, 5 neurologic, and 4 ocular involvements. All PG occurred on limbs and had typical histology with constant dermal neutrophilic infiltrate. All HS had the classical axillary-mammary phenotype. Sixty-nine percent (69%) of HS were Hurley 1 stage. Treatment consisted mainly in colchicine (n = 20), glucocorticoids (n = 12), and anti-TNFα (n = 9). Interesting results with complete or partial responses were obtained with anti-TNFα (9 cases), ustekinumab (3 cases) and tocilizumab (1 case) to treat refractory ND or HS associated with BD., Conclusion: PG seems overrepresented in patients with BD. Biotherapies such as anti-TNFα, ustekinumab and tocilizumab appear to be promising to treat refractory ND or HS associated with BD., Competing Interests: Declaration of Competing Interest None declared, (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To evaluate tocilizumab (TCZ) efficacy in patients with refractory Behçet disease (BD)., Methods: This is a multicenter study of 30 patients fulfilling the international criteria for BD and treated with TCZ at different European referral centers. The clinical response was evaluated at 6 months from TCZ initiation., Results: Ninety percent of patients with BD were refractory or intolerant to anti-tumor necrosis factor (anti-TNF) agents. Overall, TCZ was effective in 25 (83%) patients with BD of whom 18 (60%) and 7 (23%) were complete and partial responders, respectively. The complete response was 67%, 60%, and 42% in patients with uveitis (18/30), neurological manifestations (5/30), and mucocutaneous and/or articular (7/30) manifestations, respectively. TCZ had a significant steroid-sparing effect allowing patients to decrease their median daily prednisone dose from 20 (IQR 10-40) mg/day to 9 (IQR 5-13) mg at 6 months ( P < 0.001). The number of patients with BD needing concomitant disease-modifying antirheumatic drug therapy fell from 7 (23%) to 4 (13%) at 6 months. Mild to moderate side effects were observed in 6 (20%) patients, and 3 (10%) presented with serious adverse events (pneumonia, intestinal perforation, and septicemia) requiring therapy discontinuation in 2 cases., Conclusion: TCZ seems to be an effective alternative to anti-TNF agents in treating BD-related uveitis and neurological manifestations., (Copyright © 2023 by the Journal of Rheumatology.)

This French National Diagnostic and Care Protocol (NDPC) includes both pediatric and adult patients with non-infectious chronic uveitis (NICU) or non-infectious recurrent uveitis (NIRU). NICU is defined as uveitis that persists for at least 3 months or with frequent relapses occurring less than 3 months after cessation of treatment. NIRU is repeated episodes of uveitis separated by periods of inactivity of at least 3 months in the absence of treatment. Some of these NICU and NIRU are isolated. Others are associated with diseases that may affect various organs, such as uveitis associated with certain types of juvenile idiopathic arthritis, adult spondyloarthropathies or systemic diseases in children and adults such as Behçet's disease, granulomatoses or multiple sclerosis. The differential diagnoses of pseudo-uveitis, sometimes related to neoplasia, and uveitis of infectious origin are discussed, as well as the different forms of uveitis according to their main anatomical location (anterior, intermediate, posterior or panuveitis). We also describe the symptoms, known physiopathological mechanisms, useful complementary ophthalmological and extra-ophthalmological examinations, therapeutic management, monitoring and useful information on the risks associated with the disease or treatment. Finally, this protocol presents more general information on the care pathway, the professionals involved, patient associations, adaptations in the school or professional environment and other measures that may be implemented to manage the repercussions of these chronic diseases. Because local or systemic corticosteroids are usually necessary, these treatments and the risks associated with their prolonged use are the subject of particular attention and specific recommendations. The same information is provided for systemic immunomodulatory treatments, immunosuppressive drugs, sometimes including anti-TNFα antibodies or other biotherapies. Certain particularly important recommendations for patient management are highlighted in summary tables., (Copyright © 2023 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Behçet's disease (BD) is a chronic systemic vasculitis characterized by recurrent oral and genital ulcers, skin lesions, articular, neurological, vascular and sight-threatening ocular inflammation. BD is thought to share both autoimmune and autoinflammatory disease features. BD is triggered by environmental factors such as infectious agents in genetically predisposed subjects. Neutrophils seem to play an instrumental role in BD and recent works regarding the role of neutrophils extracellular traps (NETs) provides new insight in the pathophysiology of BD and the mechanisms involved in immune thrombosis. This review provides a recent overview on the role of neutrophils and NETs in the pathogenesis of BD., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: This study aimed to report the association of focal myositis (FM) and Behçet's disease (BD) and to analyse the main characteristics of such an association., Methods: This is a retrospective multicentre study of patients with BD and FM (BD + FM+ group) and those without FM (BD - FM+ group). Clinical, laboratory, radiological, pathological, treatment and outcome data were analysed., Results: The BD + FM+ group included 10 patients; the median [interquartile range] age at BD diagnosis was 25 [16-35] years, and at FM diagnosis, it was 30 [26-42] years. The diagnosis of BD preceded FM in the majority of cases (n = 8/10). FM occurrence was associated with BD flare-ups in three cases. The creatine kinase levels remained normal or slightly increased. Histological analyses identified relatively preserved muscle tissue, associated with vasculitis (n = 5/6). All patients required treatment; most patients relapsed (n = 9/10). The BD - FM+ group included 35 patients. A comparison of the groups identified a trend towards a younger median age at diagnosis of FM among those with BD (p = 0.063) and more frequent focal muscle swelling in the BD + FM+ group (p = 0.029). The pathological analysis identified significantly less frequent muscle alterations in the BD + FM+ group (muscle fibre size heterogeneity, p = 0.021; necrosis, p = 0.007; and fibrosis, p = 0.027). BD + FM+ patients had a higher frequency of relapse (p = 0.003) and systematic treatment (p = 0.042)., Conclusions: FM occurring during BD appears to be part of the systemic vasculitis process and presents as a vasculitis-associated focal myopathy with a specific clinico-histological pattern. Patients with this association require long-term follow-up and adapted management. This case series also highlights the need for research on BD diagnostic criteria in cases of FM., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Behçet syndrome is a rare, chronic inflammatory disease of unknown aetiopathogenesis, most commonly presenting with mucocutaneous and ocular manifestations. Vascular involvement, most frequently superficial vein and deep vein thrombosis, can occur in up to 50% of patients with Behçet syndrome. Venous thrombosis at atypical sites (inferior and superior vena cava, suprahepatic veins with Budd-Chiari syndrome, portal vein, cerebral sinuses and right atrium and/or ventricle) and arterial involvement (mostly in situ thrombosis and aneurysms of the pulmonary arteries, as well as aneurysms of the abdominal aorta, and peripheral and visceral arteries) are also unique features of Behçet syndrome. Behçet syndrome is considered a natural model of inflammation-induced thrombosis in humans, with an impaired immune-inflammatory response rather than traditional cardiovascular risk factors contributing to thrombogenesis. Specifically, neutrophil hyperactivation and neutrophil-mediated mechanisms of damage directly promote endothelial dysfunction, platelet activation and thrombogenesis in Behçet syndrome. This unusual pathogenesis directly determines the treatment approach, which relies mostly on immunosuppressants rather than anticoagulants for treatment of thrombosis and for secondary prevention. This Review discusses the main histopathological, pathogenetic and clinical aspects of vascular Behçet syndrome, addressing their implications for therapeutic management. Future perspectives in terms of pathogenetic studies, disease monitoring and treatment strategies are also discussed., (© 2022. Springer Nature Limited.)

Competing Interests: Competing interests: None declared.

Purpose of the Review: Emerging data suggest that regulatory T-cells (Treg) alterations play a major role in systemic vasculitis pathophysiology. We performed a systematic review of recent advances in the role of Treg and interleukin (IL)-10 in the pathogenesis and treatment of systemic vasculitis, including giant cell arteritis (GCA), Takayasu arteritis, Behçet's disease, antineutrophil cytoplasm antibodies (ANCA) associated vasculitis (AAV), and cryoglobulinemia associated vasculitis., Recent Findings: Emerging data suggest that Treg deficiencies are disease-specific, affecting distinct pathways in distinct vasculitides. Decreased peripheral blood frequencies of Treg are described in all vasculitis when compared to healthy donors. Altered Treg functions are reported in GCA, Takayasu arteritis, AAV, and Behçet's disease with different mechanisms proposed. Treatment with biologics, and sometimes other immunosuppressants, may restore Treg frequencies and/or immune activity with significant differences in active disease or disease in remission in several systemic vasculitis. IL-10 is elevated in GCA, AAV, cryoglobulinemia associated vasculitis. In Behçet's disease, IL-10 is decreased in peripheral blood and elevated in saliva. In Takayasu arteritis, IL-10 levels were essentially elevated in patients' vessel wall. Several new therapeutic approaches targeting Treg and Il-10 (low dose IL-2, CAR Treg…) are developed to treat patients with systemic vasculitis., Summary: Treg and IL-10 play a central role in the regulation of inflammation in vasculitis and new targeting approaches are emerging., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

During the last decades the efficacy of biologic agents, mainly of anti-TNFs, in controlling the activity of serious manifestations of Behcet's Disease (BD) has been established. On the other hand, the clinical heterogeneity of BD has precluded the validation of a widely-accepted composite index for disease assessment and for target disease-state definitions, such as low disease activity and remission, and the testing of their implementation in clinical practice. Therefore, in contrast to other systemic rheumatic diseases, a treat-to-target strategy has not yet been developed in BD. There are several challenges towards this approach, including standardization of outcome measures for assessing the disease activity in each-affected organ and construction of a composite disease activity index. The challenges for the development of a treat-to-target strategy and possible solutions are discussed in this position paper, which stemmed from a round table discussion that took place in the 19th International Conference on BD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Vascular Behçet's disease (VBD) is a systemic vasculitis involving both arterial and venous vessels of all sizes and occurring in up to 40% of patients with BD. VBD is the main cause of mortality in BD. Although commonly seen around the Mediterranean region, comparative studies in VBD are lacking. We aimed to compare the course and therapeutic approaches of VBD in two large cohorts from Turkey and France., Methods: We included 291 VBD patients (female/male:63/228, mean age: 41.2±11.3 years) who were followed up in the Department of Internal Medicine and Clinical Immunology at Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France (n=131) and Rheumatology Division of Marmara University School of Medicine, Istanbul, Turkey (n=160). All clinical and demographical data were acquired from patient charts retrospectively., Results: Smoking, family history for BD, HLA-B*51 presence and pathergy positivity were significantly higher in Turkish patients (TR), while neurologic involvement was more prominent in the French (FR) group. After a median follow-up of 77 months, 562 vascular events occurred including 440 venous events, 115 arterial events and 7 cardiac thrombi. In 79 (29%) patients, first vascular event developed before BD diagnosis and for 77 (28%) of them, vascular involvement was the presenting sign of the disease. First relapse developed in 130 (44.7%) patients after median 24.5 (1-276) months of follow-up (TR: 46.3% (n=74), FR: 42.7% (n=56), p=0.56). Survival graph revealed that FR cohort has 1.64 times increased recurrent event risk compared to TR cohort (HR=1.64 (1.1-2.44), p=.014) and although did not reach to statistical significance, IS treatment after the first vascular event decreased further vascular events (HR= 0.66 (0.43-1.01, p=.057)., Conclusions: Almost half of patients relapsed of VBD within 2 years after the first vascular event. Immunosuppressants decrease VBD relapses.

Objectives: Despite the remarkable efficacy of anti-TNF agents in Behçet's disease (BD), unmet therapeutic needs for refractory or intolerant patients to these drugs still exist. Based on evidence implicating IL-6 in the pathogenesis of BD, we summarise the current experience on the off-label administration of the anti-IL-6 receptor antibody tocilizumab for BD refractory to disease-modifying anti-rheumatic drugs., Methods: We searched PubMed and EMBASE for original articles published through December 2021 reporting on the use of tocilizumab for BD., Results: We retrieved 25 articles fulfilling our search criteria, reporting on a total of 74 patients of whom 31 were anti- TNF naive; 2 additional anti-TNF experienced patients were included. The vast majority (72 of 76) received the standard intravenous dose of tocilizumab, whereas the total follow-up, including also post-treatment follow-up in many patients, ranged from 2 to 84 months without new safety issues. Tocilizumab was given in anti-TNF naive patients predominantly for vascular (n=16), central nervous system (n=7) and ocular involvement (n=5). On the other hand, anti-TNF experienced patients received tocilizumab predominantly for ocular (n=28), central nervous system (n=8) and mucocutaneous involvement (n=6). Tocilizumab was effective in 87% of anti-TNF naive (13 and 14 with complete and partial remission, respectively) and in 80% of anti-TNF experienced patients (17 and 19 with complete and partial remission, respectively)., Conclusions: Although preliminary, evidence published so far suggests that IL-6 inhibition is a legitimate therapeutic option for BD patients with refractory ocular, CNS and vascular involvement. Controlled studies are clearly needed.

Behcet's disease (BD) is a multisystemic vasculitis involving arteries and veins of all sizes. While joint and dermatological manifestations are the most common features of BD and are associated with a good prognosis; vascular involvement, remains the principal cause of death. Arterial manifestations occur in 5-10% of cases and manifest as occlusion/thrombosis or aneurysms. Arterial aneurysms are likely multiple and the most common sites are pulmonary arteries, aorta and arteries of lower limbs. Parenchymal involvement is less frequent and may manifest as consolidation or nodules, which may evolve to excavation. Aneurysms may occur at the sites of arterial puncture; then, non-traumatic techniques are favored. Patients with arterial manifestations may present with fever and increased inflammatory markers. Artery damage is rare, serious, and may result in massive hemoptysis. The prognosis of pulmonary artery aneurysms is severe (mortality estimated up to 26%) but has been improved by earlier diagnosis and the introduction of immunosuppressants. Treatment of severe arterial manifestations is based on high-dose corticosteroids along with cyclophosphamide or anti-TNF antagonists. Anticoagulation could be added to immunosuppressants in case of venous thrombosis if a coexisting pulmonary aneurysm is ruled out. Endovascular treatment should be performed in case of severe symptomatic pulmonary aneurysms, along with an adequate medical management. Long-term maintenance therapy of these severe forms is of paramount importance because of relapse risk (40% at five years)., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: To compare the relapse rate of sight-threatening noninfectious uveitis (NIU) in patients treated with infliximab (IFX) or adalimumab (ADA)., Design: Observational retrospective multicenter study., Methods: A total of 330 patients (median age, 36 years; interquartile range, 27-54), 45.2% men) with sight-threatening NIU (ie, retinal vasculitis and/or macular edema) treated with anti-tumor necrosis factor [TNF]-α agents (IFX intravenously at 5 mg/kg at weeks 0, 2, 6, and every 4 to 6 weeks or ADA subcutaneously at 80 mg, then 40 mg every 2 weeks). Data were obtained retrospectively from patients' medical records. Main outcome measures were relapse rate, complete response of NIU, corticosteroid sparing effect, and safety., Results: Main etiologies of uveitis included Behçet disease (27%), idiopathic juvenile arthritis (5.8%), and sarcoidosis (5.5%). The estimated relapse rate at 6 months after introduction of biological agents was 13% (95% CI = 0.009-0.16). IFX was associated with less relapse risk than ADA (hazard ratio [HR] = 0.52, 95% CI = 0.36- 0.77, P = .001). ADA and IFX were comparable in terms of complete response rate of NIU as well as corticosteroid-sparing effect. Behçet disease was associated with higher odds of complete response (HR = 2.04, 95% CI = 1.16 -3.60, P = .01] and lower relapse rate (HR = 0.53, 95% CI = 0.33-0.85, P = .009) than other causes of NIU with anti-TNF-α agents., Conclusions: In sight-threatening NIU, IFX seems to be associated with a lower relapse rate than ADA., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To examine the mortality rates and causes of death among French decedents with Behçet's disease (BD)., Methods: Data collected between 1979 and 2016 by the French Epidemiological Center for the Medical Causes of Death was used to calculate BD-related mortality rates and examine differences according to age and sex, determine underlying and non-underlying causes of death (UCD/NUCD), and compare with the general population (observed/expected ratios, O/E)., Results: A total of 328 death certificates mentioned BD as UCD (n = 171) or NUCD (n = 157). The mean (± SD) age at death was 52.8 (± 11.3) years in men and 58.4 (± 16.5) in women (vs. 71.2 and 79.8 in the general population, respectively). The age-standardized mortality rate was 0.15/million person-years and significantly increased over the study period (p < 0.01). When BD was the UCD, the most frequent associated causes were infections (25.1%), underlying organ dysfunction (21.6%), and arterial events (15.2%). As compared to the general population, BD decedents < 45 years were more likely to die from a cardiovascular event (O/E = 6.25, p < 0.001); decedents > 45 years were more likely to die from infection (O/E = 9.69, p < 0.001). Between 1979 and 2016, BD as UCD decreases whereas NUCD increased., Conclusion: This study found an earlier mean age at death for BD compared to the general population; young patients were more prone to die from cardiovascular complication whereas older patients died more frequently from infections. Over the years, the mean age at death increased and BD was less frequently considered as an UCD, suggesting a better knowledge of the disease and complications. Key Points • Patients with Behçet's disease die earlier than the general population. • Young patients were more prone to die from cardiovascular complication. • Older patients died more frequently from infections., (© 2021. International League of Associations for Rheumatology (ILAR).)

Objectives: Behçet disease (BD) is a chronic systemic inflammatory disorder of unknown aetiology. The aim of this study was to determine the orientation of T cell subpopulations in paediatric BD and more precisely to look for a regulatory T lymphocyte (Treg)/Th17 imbalance., Methods: T cell subpopulations were analysed by flow cytometry in the peripheral blood of paediatric patients with acute BD (aBD; n = 24), remitting BD (rBD; n = 12) and in healthy controls (HCs; n = 24). Tregs (CD4+CD25hiCD127-/loFoxp3+), activated Tregs (GITR, LAP, CTLA-4 and HLA-DR expression), CD4+ and CD8+ T cells producing IFN-γ (Th1 and Tc1) or IL-17 (Th17 and Tc17) under polyclonal (OKT3/IL-2) or antigenic (Streptococcus sanguis KTH-1 peptides and heat shock protein 60) stimulation were enumerated., Results: Th17 (1.9- and 5.1-fold) and Tc17 (4.0- and 2.0-fold) frequency under mitogenic stimulation was significantly increased in aBD and rBD patients as compared with HCs. Th17 frequency under antigenic stimulation was also higher in patients than in HCs. The percentage and number of Tregs and activated Tregs in patients and in HCs were similar. However, when Tregs were removed, antigen-driven differentiation into Th1 and Th17 was significantly boosted in BD but not in HC CD4+ T cells., Conclusion: There is a bias towards Th17 polarization in aBD and rBD in children. Although we did not observe an increase in the number of Tregs in these patients, their Tregs limit CD4+ T cell differentiation into Th1 and Th17 cells. Thus, in paediatric BD, Tregs seem to incompletely counterbalance a Th17 orientation of the Th cell response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study assessed the efficacy and safety of apremilast for the oral ulcers associated with Behçet's syndrome (BS) up to 64 weeks., Methods: The phase 3, double-blind, placebo-controlled RELIEF study randomised adult patients with active BS to placebo or apremilast 30 mg twice daily for 12 weeks, followed by an extension phase with all patients receiving apremilast through Week 64 and 4-week post-treatment follow-up (upon treatment discontinuation). The primary endpoint was area under the curve for the number of oral ulcers over 12 weeks (AUCWk0-12), reflecting the number of oral ulcers over time and accounting for their recurring-remitting course. Oral ulcer number, complete and partial responses, pain and disease activity and quality of life (QoL) were also assessed throughout the study., Results: A total of 207 participants were randomised and received at least one dose of study medication; 178 entered the extension phase and 143 completed Week 64. AUCWk0-12 was significantly lower with apremilast versus placebo (p<0.0001), and oral ulcers number, pain, complete/partial responses, disease activity and QoL with apremilast versus placebo showed improvements at Week 12, which were maintained through Week 64. The most common adverse events were diarrhoea, nausea, headache and upper respiratory tract infection; no new safety concerns were observed with longer-term apremilast exposure., Conclusions: In patients with oral ulcers associated with BS, apremilast was efficacious and benefits were sustained up to 64 weeks with continued treatment. Apremilast was well tolerated, and safety was consistent with its known safety profile.

Introduction : Noninfectious uveitis (NIU) is one of the leading causes of blindness worldwide. In adult patients, anterior NIU is usually managed with topical corticosteroids. In intermediate, posterior uveitis. and panuveitis, systemic corticosteroids are used especially in case of bilaterality or association with systemic disease. Biotherapies are recommended in case of inefficacy or intolerance to corticosteroids or conventional immunosuppressive drugs. Anti-TNF-α agents are by far the most widely used biotherapies. In case of failure or poor tolerance to anti-TNF-α, new targeted therapies can be proposed. Areas covered : We present and discuss an updated overview on biologics and biotherapies in NIU. Expert opinion : In case of dependency to systemic or intravitreal steroids, sight-threatening disease, and/or failure of conventional immunosuppressive drugs, anti-TNF-α are used as first-line biologics to achieve quiescence of inflammation. Anti-interleukin-6 is another option that may be proposed as first-line biologic or in case of poor efficacy of anti-TNF-α. Interferon can be directly proposed in specific indications (e.g. refractory macular edema, sight-threatening Behçet's uveitis). In the rare cases that remain unresponsive to traditional biotherapies, novel molecules, such as Janus-associated-kinase and anti-phosphodiesterase-4-inhibitors can be used. Therapeutic response must always be evaluated by clinical and appropriate ancillary investigations.

Behçet's disease (BD) is a systemic variable vessel vasculitis that involves the skin, mucosa, joints, eyes, arteries, veins, nervous system and gastrointestinal system, presenting with remissions and exacerbations. It is a multifactorial disease, and several triggering factors including oral cavity infections and viruses may induce inflammatory attacks in genetically susceptible individuals. BD vasculitis involves different vessel types and sizes of the vascular tree with mixed-cellular perivascular infiltrates and is often complicated by recurrent thrombosis, particularly in the venous compartment. Several new therapeutic modalities with different mechanisms of action have been studied in patients with BD. A substantial amount of new data have been published on the management of BD, especially with biologics, over the last years. These important therapeutic advances in BD have led us to propose French recommendations for the management of Behçet's disease [Protocole National de Diagnostic et de Soins de la maladie de Behçet (PNDS)]. These recommendations are divided into two parts: (1) the diagnostic process and initial assessment; (2) the therapeutic management. Thirty key points summarize the essence of the recommendations. We highlighted the main differential diagnosis of BD according to the type of clinical involvement; the role of genetics is also discussed, and we indicate the clinical presentations that must lead to the search for a genetic cause.

Objective: Mucocutaneous and joint disorders are the most common manifestations in Behçet's syndrome (BS) and are frequently clustered in the so-called minor forms of BS. There remains a need for safe and effective treatment for joint lesions in BS. We report the long-term safety and effectiveness of apremilast in refractory joint and mucocutaneous manifestations of BS., Methods: French nationwide multicenter study including 50 BS patients with either active joint and/or mucocutaneous manifestations resistant to colchicine and/or DMARDs. Patients received apremilast 30 mg twice a day. Primary effectiveness endpoint was the proportion of patients with complete response (CR) of articular symptoms at month 6 (M6), defined as resolution of inflammatory arthralgia and arthritis, with joint count equal to zero., Results: At inclusion, the median tender and swollen joint count was of 4 [2-6] and 2 [1-2], respectively. The proportion of CR in joint disease at M6 was 65% (n = 15/23), and 17% (n = 4/23) were partial responders. CR of oral and genital ulcers, and pseudofolliculitis at M6 was 73% (n = 24/33), 94% (n = 16/17) and 71% (n = 10/14), respectively. The overall response at M6 was 74% for the entire cohort and 70% for the mucocutaneous-articular cluster (n = 27). The median Behçet's syndrome activity score significantly decreased during study period [50 (40-60) vs. 20 (0-40); p < 0.0001]. After a median follow-up of 11 [6-13] months, 27 (54%) patients were still on apremilast. Reasons for apremilast withdrawal included adverse events (n = 15, 30%) and treatment failure (n = 8, 16%). Thirty-three (66%) patients experienced adverse events, mostly diarrhea (n = 19, 38%), nausea (n = 17, 34%) and headache (n = 16, 32%)., Conclusion: Apremilast seems effective in BS-related articular disease refractory to colchicine and DMARDs. Discontinuation rates were significantly higher than that reported in clinical trials., Competing Interests: DS reports grants and personal fees from AMGEN, during the conduct of the study, grants and personal fees from ABBVIE, grants and personal fees from ROCHE-CHUGAI, grants and personal fees from SANOFI, and grants from GSK, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vieira, Buffier, Vautier, Le Joncour, Jamilloux, Gerfaud-Valentin, Bouillet, Lazaro, Barete, Misery, Gobert, Goulenok, Fain, Sacre, Sève, Cacoub, Comarmond and Saadoun.)

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., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Oral ulcers, the hallmark lesion of Behçet's disease (BD), can be disabling and resistant to conventional treatment, and there is a need for safe and effective treatment. We undertook this study to investigate the long-term safety and efficacy of ustekinumab therapy for BD-related oral ulcers that are resistant to colchicine., Methods: This multicenter, prospective, open-label study included 30 patients who fulfilled the criteria of the International Study Group for BD and who were diagnosed as having active oral ulcers resistant to colchicine. Patients were treated subcutaneously with ustekinumab 90 mg at inclusion, at week 4, and then once every 12 weeks. Each patient was assessed longitudinally for the presence and number of oral ulcers, and median numbers of oral ulcers (with interquartile range [IQR]) were calculated. The primary efficacy end point was the proportion of patients at week 12 who experienced complete response, defined as having no oral ulcers., Results: The median number of oral ulcers per patient during ustekinumab therapy was significantly lower at week 12 compared to baseline (0 [IQR 0-1] versus 2 [IQR 2-3]; P < 0.0001). Complete response was achieved in 60.0% and 88.9% of patients at weeks 12 and 24, respectively. The median Behçet's Syndrome Activity Score (in which higher scores indicate more active disease) was significantly lower at weeks 12 and 24 (17.5 [IQR 10-42.5] and 10 [IQR 8-11], respectively) versus baseline (70 [IQR 50-70]; P < 0.0001). After a median follow-up of 12 months (IQR 6-16 months), 26 patients (86.7%) were still receiving ustekinumab treatment. Reasons for ustekinumab discontinuation included BD flare (n = 3) and side effects (n = 1). Seven patients (23.3%) experienced adverse events, including headaches (n = 4) and asthenia (n = 2), with no serious side effects., Conclusion: Ustekinumab seems to be effective in treating BD-related oral ulcers that are resistant to treatment with colchicine., (© 2019, American College of Rheumatology.)

Objectives: Behçet's disease (BD) is a chronic systemic vasculitis. Thrombosis is a frequent and life-threatening complication. The pathogenesis of BD is poorly understood and evidence supporting a role for primed neutrophils in BD-associated thrombotic risk is scant. To respond to inflammatory insults, neutrophils release web-like structures, known as neutrophil extracellular traps (NETs), which are prothrombotic. We evaluated the role of NETs and markers of NETs in BD., Methods: Blood samples were collected from patients with BD, according to the International Study Group Criteria for Behçet's disease, and healthy donors (HD). NET components, including cell-free DNA (CfDNA) and neutrophil enzymes myeloperoxidase (MPO), were assessed in serum or in purified neutrophils from patients with BD and HD., Results: Patients with active BD had elevated serum cfDNA levels and MPO-DNA complexes compared with patients with inactive BD and to HD. In addition, levels of cfDNA and MPO-DNA complexes were significantly higher in patients with BD with vascular involvement compared with those without vascular symptoms. Purified neutrophils from patients with BD exhibited spontaneous NETosis compared with HD. Thrombin generation in BD plasma was significantly increased and positively correlated with the levels of MPO-DNA complexes and cfDNA. Importantly, DNAse treatment significantly decreased thrombin generation in BD plasma but not in HD plasma. In addition, biopsy materials obtained from patients with BD showed NETs production in areas of vasculitic inflammation and thrombosis., Conclusions: Our data show that NETs and markers of NETS levels are elevated in patients with BD and contribute to the procoagulant state. Targeting NETs may represent a potential therapeutic target for the reduction or prevention of BD-associated thrombotic risk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim of this systematic review was to inform the update of European League Against Rheumatism (EULAR) Recommendations for the management of Behçet's syndrome (BS), on the evidence for the treatment of skin, mucosa and joint involvement of BS., Methods: A systematic literature search, data extraction, statistical analyses and assessment of the quality of evidence were performed according to a pre-specified protocol using the PRISMA guidelines. Studies that assessed the efficacy of an intervention in comparison to an active comparator or placebo for oral ulcers, genital ulcers, papulopustular lesions, nodular lesions or arthritis were included. Where possible, risk ratios were calculated for binary outcomes and mean difference for continuous outcomes., Results: Among the 3927 references that were screened, 37 were included in the analyses. Twenty-seven of these assessed mucocutaneous and 17 assessed joint involvement. Twenty-one of these studies were randomised controlled trials (RCTs). RCTs with colchicine, azathioprine, interferon-alpha, thalidomide, etanercept and apremilast showed beneficial results with some differences according to lesion type and gender. These agents were generally well tolerated with few adverse events causing withdrawal from the study., Conclusions: RCTs comprised more than a half (21/37, 57%) of the sources included in the evidence synthesis related to skin, mucosa and joint involvement applicable for the EULAR Recommendations for the management of BS. Differences in the outcome measures that were used across the included studies often made it difficult to combine and compare the results., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The neuro-ophthalmological manifestations of Behcet's disease (BD) are rare, and data regarding their characteristics and outcome are lacking., Objective: To report prevalence, main characteristics and outcome of neuro-ophthalmological manifestations in BD., Patients and Methods: This is a retrospective monocentric study of 217 patients diagnosed with neuro-Behçet's disease (NBD), of whom 29 (13.3%) patients presented with neuro-ophthalmological manifestations (55% of men and mean±SD age of 26±8 years). All patients underwent a detailed ophthalmological examination and were followed up in the internal medicine and the ophthalmology departments., Results: Neuro-ophthalmological manifestations were the first presentation of BD in 45% of patients and developed later in the course of the disease in 55% of patients. They are divided into parenchymal (PM) and non-parenchymal (NPM)-related manifestations in, respectively, 13 patients (45%) and 16 patients (55%). PM included papillitis in seven patients (53.8%), retrobulbar optic neuritis in four patients (30.8%) and third cranial nerve palsy in two patients (15.4%). NPM included papilloedema related to cerebral venous thrombosis in all 16 patients, of whom 6 patients (37.5%) had sixth cranial nerve palsy. At initial examination, 93.1% of patients had visual alterations, including mainly decreased visual acuity visual field defects and/or diplopia. All patients were treated with corticosteroids and 79% of patients received immunosuppressive agents. After treatment, the visual outcome improved or stabilised in 66.7% of patients while it worsened in 33.3. The mean±SD logarithm of the minimum angle of resolution visual acuity improved from 0.4±0.3 at diagnosis to 0.2±0.3 after therapy. 10.3% and 3.4% of patients were legally blind at diagnosis and after therapy, respectively., Conclusion: Neuro-ophthalmological manifestations of BD represented 13% of NBD. They could be potentially severe and disabling. Prompt treatment is the key factor in improving visual outcome., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD)., Methods: A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents., Results: Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42-62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1)., Conclusion: TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To assess the efficacy and safety of treatment modalities for major organ involvement of Behçet's syndrome (BS), in order to inform the update of the EULAR recommendations for the management of BS., Methods: A systematic literature review of all randomized controlled trials, controlled clinical trials, or open label trials assessing eye, vascular, nervous system or gastrointestinal system involvement of BS was performed. If controlled trials were not available for answering a specific research question, uncontrolled studies or case series were also included., Results: We reviewed the titles and abstracts of 3927 references and 161 studies met our inclusion criteria. There were only nine randomized controlled trials. Observational studies with IFN-α and monoclonal anti-TNF antibodies showed beneficial results for refractory uveitis. Meta-analysis of case-control studies showed that immunosuppressives decreased the recurrence rate of deep vein thrombosis significantly whereas anticoagulants did not. CYC and high dose glucocorticoids decreased mortality in pulmonary arterial aneurysms and postoperative complications in peripheral artery aneurysms. Beneficial results for gastrointestinal involvement were obtained with 5-ASA derivatives and AZA as first line treatment and with thalidomide and/or monoclonal anti-TNF antibodies in refractory cases. Observational studies for nervous system involvement showed improved outcome with immunosuppressives and glucocorticoids. Meta-analysis of case-control studies showed an increased risk of developing nervous system involvement with ciclosporin-A., Conclusion: The majority of studies related to major organ involvement that informed the updated EULAR recommendations for the management of BS were observational studies.

Ocular disease in Behçet's disease is frequent and may be associated with a poor functional prognosis. Uveitis is the most common ocular manifestation in Behçet's disease and represents a diagnostic criterion of the disease. The ocular involvement is inaugural of the disease in 20% of the cases or may develop 2 to 3 years after the beginning of the extraocular signs. The risk of blindness at 5 years is in the order of 15 to 25%, mainly due to macular involvement or retinal vasculitis. Uveitis may be anterior, intermediate, posterior or panuveitis. Anterior uveitis is rarely isolated and is frequently accompanied by posterior involvement. Anterior uveitis is always non granulomatous, sometimes associated with hypopion. Posterior involvement may include the presence of hyalitis, retinal vasculitis, mainly venous and often occlusive, macular edema, and/or foci of necrotizing retinitis. Behçet's disease is a chronic disorder, characterized by a relapsing and remitting course. Male patients with younger age at onset and severe lesions at presentation are at higher risk of severe visual loss over time. The main goals in the management of patients with Behçet's disease-associated uveitis are rapid suppression of intraocular inflammation, preservation of vision, and prevention of recurrences. The treatment is based on the use of systemic glucocorticosteroids and immunosuppressive agents. Posterior segment involvement requires the use of corticosteroids and immunosuppressants, primarily azathioprine. This treatment does not appear to be sufficient for severe uveitis with reduced visual acuity or retinal vasculitis that requires anti-TNF α or interferon α. Therapeutic strategies such as TNF-alpha blockers have dramatically improved the visual prognosis of patients with intraocular inflammation related to this chronic and potentially blinding condition., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Several new treatment modalities with different mechanisms of action have been studied in patients with Behçet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities., Competing Interests: Competing interests: BB received consultant fees from Santen, AbbVie, Allergan, Xoma and research grants from Novartis and Bayer. ITT received honoraria from Servier, AbbVie and Allergan. GH received research grants from Celgene, honoraria from Pfizer and speaker’s fees from Abbvie, MSD and UCB., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

There is as yet no consensus on the treatment of cerebral venous thrombosis (CVT) in Behçet's disease, and the place of anticoagulation is also still being debated. This report is of a series of seven patients with Behçet's disease (BD)-associated CVT, for which anticoagulation was stopped, and discusses the possibility of stopping anticoagulation during follow-up while receiving optimal treatment for BD. The diagnosis of BD was established during follow-up, which lasted a median of 120 [range: 60-1490] days after CVT diagnosis. The median duration of anticoagulation therapy was 29.5 months. On stopping anticoagulation, concomitant treatment then included colchicine, steroids and azathioprine, all introduced after BD was diagnosed. With a median follow-up of 25 months after anticoagulation interruption, only one relapse of CVT was observed. No relapse of CVT or other venous thrombosis was observed in the six patients treated by steroids associated with an immunosuppressant or colchicine. Our results emphasize that corticosteroids are essential for the treatment of BD-associated CVT, and that anticoagulant therapy may be safely stopped during follow-up in the presence of optimal BD treatment (steroids alone or with immunosuppressive drugs)., (Copyright © 2017. Published by Elsevier Masson SAS.)

Objective: To evaluate the efficacy and safety of ustekinumab in the treatment of oral ulcers (OU) in patients with Behçet's disease (BD)., Patients and Methods: Prospective study including 14 patients [median age of 39 (34; 41) years, with 71% of men] fulfilling criteria of the International Study Group for BD and with active OU resistant to colchicine. Patients received ustekinumab 90 mg (n = 11) or 45 mg (n = 3) subcutaneously at inclusion, at week 4, and every 12 weeks. The primary efficacy endpoint was the proportion of patients with complete response (CR), defined as no oral ulcer, at week 12., Results: At week 12, 64% were in CR, 21% in partial response and 14% non-responders. The median number of OU decreased from 2 [2; 4] to 1 [0; 1.25] (p = 0.0005) at week 12. Mean change from baseline to week 12 of Behçet's syndrome activity score (BSAS) was 22.8 ± 0.3 (p = 0.01). The median daily corticosteroids dose decreased from 12.5 (10; 16.3) to 5 [5; 10] mg/day (p = 0.02). Three patients reported headaches, leading to discontinuation of ustekinumab in one case. After a median follow-up of 7 [3; 12] months, 10 (71%) patients were still receiving ustekinumab and four (28%) experienced a relapse. Decreased levels of circulating IL-17 and IL-12 [median [IQR]; 3.9 [1.6; 10.6] vs. 29.2 [25.2; 42.7] pg/ml, and 29.4 [23.1; 33.3] vs. 56.1 [51.1; 64.4] pg/ml, p = 0.008 for both] were observed under ustekinumab, respectively., Conclusion: Ustekinumab seems to be efficient and safe for patient with BD and refractory OU although relapses are frequent., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The efficacy of anti-TNFα agents has been recently evaluated in many studies in Behçet's disease (BD), particularly in ocular and life-threatening manifestations such as neurological and vascular disease. Areas covered: The following article aims to summarize the currently available efficacy and safety data of anti-TNFα agents in BD. Expert opinion: Most studies have shown dramatic and rapid efficacy with anti-TNFα agents on the main BD-associated issues including posterior uveitis, gastro-intestinal and neurological complications as well as major vessel disease. Experts in the field do recommend the use of anti-TNF agents (either infliximab or adalimumab) as a first-line therapy in severe posterior uveitis in BD and now use anti-TNFα treatment in BD-associated life threatening manifestations. However, data is mainly based on retrospective cohorts or open-label prospective studies. Controlled studies (versus conventional immunosuppressants such as azathioprine and cyclophosphamide) are warranted to properly evaluate their efficacy as first line therapeutic in life-threatening manifestations of BD.

Purpose: To retrospectively assess the frequency of ocular relapse and the possibility of long-term remission in patients treated with interferon (IFN) for severe uveitis associated with Behçet disease., Methods: All patients were treated with an initial dosage of 3 million IU IFN three times a week. The main outcome measure was the number of relapses per person per year before, during, and after IFN treatment., Results: Of 36 patients (67 eyes), 31 (86.1%) responded to IFN. The mean follow-up was 8.19 years. Twenty-one out of 36 patients discontinued IFN and 76% of these have not relapsed within 5.05 years after discontinuation. The mean relapse per person per year decreased significantly from 1.39 to 0.0496 (p = 1.82×10 -10 ) during the treatment period and remained at 0.057 relapses per person per year after IFN discontinuation., Conclusion: IFN efficiently decreases the relapse rate and seems to permit long-term remission even after discontinuation.

To report the safety and efficacy of anti-tumor necrosis factor α (TNFα) therapy in severe and refractory neuro-Behçet disease (NBD) patients.Observational, multicenter study including 17 BD patients (70.6% of male, with a median age of 39.3 [24-60] years), with symptomatic parenchymal NBD, refractory to previous immunosuppressant and treated with anti-TNFα (infliximab 5 mg/kg [n = 13] or adalimumab [n = 4]). Complete remission was defined by the disappearance of all neurological symptoms and by the improvement of radiological abnormalities at 12 months.Overall improvement following anti-TNF was evidenced in 16/17 (94.1%) patients including 6 (35.3%) complete response and 10 (58.8%) partial response. The median time to achieve remission was 3 months (1-6). The median Rankin score was 2 (1-4) at the initiation of anti-TNFα versus 1 (0-4) at the time of remission (P = 0.01). Corticosteroids have been stopped in 4 (23.5%) patients, and reduced by more than 50% as compared with the dosage at baseline in 10 (58.8%) patients. Side effects occurred in 23.5% of patients and required treatment discontinuation in 17% of cases.TNF blockade represents an effective therapeutic approach for patients with severe and refractory NBD, a difficult to treat population.

Giant cell arteritis (GCA) and Takayasu's arteritis (TA) are large vessel vasculitis (LVV) and aortic involvement is not uncommon in Behcet's disease (BD) and relapsing polychondritis (RP). Glucocorticosteroids are the mainstay of therapy in LVV. However, a significant proportion of patients have glucocorticoid dependance, serious side effects or refractory disease to steroids and other immunosuppressive treatments such as cyclophosphamide, azathioprine, mycophenolate mofetil and methotrexate. Recent advances in the understanding of the pathogenesis have resulted in the use of biological agents in patients with LVV. Anti-tumor necrosis factor-α drugs seem effective in patients with refractory Takayasu arteritis and vascular BD but have failed to do so in giant cell arteritis. Preliminary reports on the use of the anti-IL6-receptor antibody (tocilizumab), in LVV have been encouraging. The development of new biologic targeted therapies will probably open a promising future for patients with LVV., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The arterial lesions affect about 10% of patients with Behçet's disease (BD). Aortic inflammatory involvement includes predominantly aortic aneurysmal lesions affecting most often the abdominal aorta. They account for the severity of the disease and are a leading cause of death when they hit the aorta or pulmonary arteries. Within the arterial lesions of BD, aortic involvement is, with femoral lesions, the most common site involved (18-28% of patients with vascular disease). Unlike other large vessels vasculitis (i.e. giant cell arteritis and Takayasu's arteritis) diffuse aortitis is observed in less than 5% of patients with BD. Aortic lesions of BD may be asymptomatic (systematic imaging or occasionally associated with other vascular event) or be revealed by the occurrence of abdominal, thoracic or lumbar pain, or an aortic valve insufficiency. Fever is frequently associated. Increase in acute phase reactants is common in these patients. Histological analysis may show infiltration by lymphocytes, neutrophils and plasma cells in the media and adventitia and a proliferation of the vasa vasorum in the media as well as a fibroblastic proliferation. In the later phase, a fibrous thickening of the media and adventitia is observed as well as a proliferation and thickening of the vasa vasorum. The therapeutic management should always include a medical treatment for the control of inflammation (corticosteroids, immunosuppressive drugs and/or biotherapy) and often an endovascular or surgical treatment if the aneurysm is threatening. The choice between endovascular or surgical treatment is considered case by case, depending on the experience of the team, anatomical conditions and of the clinical presentation. In this review, we provide a detailed and updated review of the literature to describe the aortic inflammatory damage associated with Behçet's disease., (Copyright © 2015 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Objective: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD)., Methods: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]., Results: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 [0.12-0.89]; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 [7-36] months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases., Conclusion: Anti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background and Aims: Interferon alpha (IFN-α) is an effective treatment for patients with active Behçet disease (BD). Besides its antiviral property, IFN-α is a cytokine with pleiotropic effects that can generate an anti-inflammatory environment or inhibit specific inflammatory T cells such as Th1 and Th17 cells. However, it is not known, in BD patients, whether IFN-α inhibits pro inflammatory T cells, or induces anti-inflammatory properties in T cells., Methods: Total memory CD45RO(+) T cells purified from peripheral blood mononuclear cells (PBMCs) obtained from patients with active BD (N=5), systemic lupus erythematosus (SLE, N=5) or healthy control (HC, N=6) were cultured in vitro with or without IFN-α. Levels of IFN-γ, IL-17, IL-10, IL-6, and TNF-α in the supernatants were analyzed by ELISA, Cytometric Beads Array (CBA) or intracellular cytokine staining. We analyzed the production of IL-10 on the memory subsets Th1 (mTh1), Th2 (mTh2) and Th17 (mTh17)., Results: IFN-α significantly increased IFN-γ level in memory CD4(+) T cells in BD patients and HC, but not SLE patients. IL17 was not inhibited by IFN-α in BD or in SLE patients. However, IFN-α modulated the pro- and anti-inflammatory cytokines secreted by T cells as it increased the IL-10/IL-6 ratio in BD and HC, but not SLE patients. We further demonstrated that IFN-α increased IL-10 secretion in each memory subset mTh1, mTh2 and mTh17., Conclusions: In BD, IFN-α promotes a regulatory Th1 response through IL-10 secretion. This effect may explain the efficacy of IFN-α in inflammatory disease., (Copyright © 2014. Published by Elsevier B.V.)

Background: Behcet's disease (BD) is a well-known cause of Budd-Chiari syndrome (BCS). Data are lacking on the presentation and outcome of BCS related to BD., Methods: We investigated the relationship between BD and BCS in 14 patients with both diseases and compared the results to 92 BCS patients without BD., Results: Male gender (p = 0.003), North African origin (P = 0.007) and inferior vena cava obstruction (P < 0.0001) were more frequent in patients with BD and BCS than in those with BCS alone and the plasma C-reactive protein level was higher (p = 0.003). Two of the patients with the combined diseases underwent recanalization of the vena cava and the hepatic veins, none received transjugular intrahepatic portosystemic shunts (TIPS), one received a surgical shunt and one underwent liver transplantation. TIPS were less frequent in patients with BD and BCS than in those with BCS alone (P = 0.019). Eighty six per cent of patients with BCS and BD received corticosteroids and immunosuppressive therapy. The 5-year transplantation-free survival rate was 63% in patients with BCS alone and 91% in those without BD (P = 0.11). In our series and in the literature, a high number of patients [12 (61.5%) and 11 (64.7%) respectively] treated with anticoagulation and corticosteroids and/or immunosuppressants did not require invasive treatment., Conclusion: This study shows a higher frequency of IVC obstruction in patients with BCS and BD. Medical treatment with anticoagulation and immunosuppressive agents may improve the symptoms of BCS. Therefore early management with immunosuppressive and anticoagulation therapy appears to be the treatment of choice in patients with BCS and BD.

Objectives: To report the safety and efficacy of tocilizumab in patients with severe and refractory non-infectious uveitis., Methods: Eight consecutive unselected patients with severe and refractory non-infectious uveitis [Birdshot chorioretinopathy (n=1), Behçet's disease (n=1) and idiopathic bilateral panuveitis (n=6)] treated with tocilizumab (8mg/kg every 4 weeks intravenously) were included. The primary outcome was the response to treatment, defined by decrease of inflammatory ocular signs., Results: Four (50%) patients were of female gender and the median (IQR) age was 41 (31-47) years. The median number of previous immunosupressants was of 5.5 (4-6.7). Seven patients had been previously treated with anti-TNF-α [infliximab (n=5) and adalimumab (n=2)]. The immunosupressive drugs used in association with tocilizumab were azathioprine (n=2), mycophenolate mofetil (n=2) and methotrexate (n=2). After a median follow-up of 8 months (6-25), 6/8 (75%) improved under tocilizumab and 2 (25%) were non-responders. The visual acuity improved in five patients. The median dose of prednisolone decreased from 16mg/day (10.6-20.5) to 10 mg/day (10-13.7), at baseline and at the end of follow-up, respectively. Tolerance of tocilizumab was satisfactory and side effects included bronchitis (n=1) and grade 1 leukopenia (n=1) and thrombocytopenia (n=1)., Conclusions: Tocilizumab seems to be a safe and promising therapy in severe and refractory non-infectious uveitis.

Behçet's disease (BD) is a systemic large-vessel vasculitis characterized by a wide clinical spectrum including recurrent oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations. Therapeutic management of BD depends on the clinical presentation and organ involved. Although colchicine, nonsteroidal antiinflammatory agents and topical treatments with corticosteroids are often sufficient for mucocutaneous and joint involvements, more aggressive approach with immunosuppressive agents is warranted for severe manifestations such as posterior uveitis, retinal vasculitis, vascular, and neurological and gastrointestinal involvements. However, some patients still have refractory disease, relapse, sight threatening eye disease, or irreversible organ damage. Recent improvements in the understanding of the pathogenic mechanisms have led to the identification of potential targets and future biological therapies for BD. In contrast to current non-specific immunosuppressive agents, the emergence of biotherapies provides the possibility of interfering with specific pathogenic pathways. Novel targeted biotherapies might be used in the future for BD., (Copyright © 2014 Elsevier B.V. All rights reserved.)