Epidemiology of systemic vasculitis.

PURPOSE OF REVIEW: Epidemiology of vasculitides exhibit geographic variation and data from some parts of the world are still scarce. Increased recognition of these rare diseases and improvement in diagnosis and patient care may lead to changes in their epidemiology. In this review, we aimed to highlight the most recent work on the epidemiology of systemic vasculitis. RECENT FINDINGS: New data from countries where information on the epidemiology of giant cell arteritis, Takayasu arteritis and Behçet syndrome were limited have revealed that these conditions are not as rare as previously believed. The incidence rates during the coronavirus disease 2019 pandemic highlight the link between Kawasaki disease and respiratory pathogens. The use of different classification criteria hampers the comparison of true incidence and prevalence rates in antineutophil cytoplasmic antibody (ANCA)-associated vasculitis and its subtypes between geographies and over time. SUMMARY: Recent studies have highlighted the epidemiology of vasculitides in different parts of the world and changing trends. Standardization of study design and disease definitions is needed to improve the reliability and comparability of the results.

Validation of the Behçet's Syndrome Overall Damage Index (BODI) for Retrospective Studies and a Proposal for Modification.

OBJECTIVE: Assessment of damage accrual over time is important for evaluating and comparing long-term results of treatment modalities and strategies. Retrospective studies may be useful for assessing long-term damage, especially in rare diseases. We aimed to validate Behçet's Syndrome Overall Damage Index (BODI) for use in retrospective studies by evaluating its construct validity, reliability, and feasibility in retrospectively collected data. Additionally, we aimed to determine missing items by evaluating Behçet's syndrome patients with different types of organ involvement and long-term follow-up. METHODS: We included 300 patients who had at least 2 clinic visits at 1-year intervals. The construct validity for use in retrospective trials was assessed by comparing BODI scores calculated from patient charts and during face-to-face visits. BODI was additionally scored using retrospective chart data by 2 different observers and by the same observer six months apart, in a blinded manner. The time for filling BODI was evaluated to assess feasibility. Additionally, damaged items that were missing from BODI were identified. RESULTS: There was a good correlation between the retrospective and face-to-face evaluation of BODI (ICC 0.99; %95 CI 0.99-0.99). Inter-observer and intra-observer agreement were good (ICC 0.96 and 1, respectively). The main damage items that BODI did not capture were hypertension, liver failure, lung parenchymal involvement, glaucoma, and lymphedema. CONCLUSION: BODI seems to be a reliable and feasible instrument for assessing damage in retrospective studies. Modifying BODI using the additional damage items identified in this study may make it an even better scale.

Pulmonary artery involvement due to Behçet's syndrome and Hughes Stovin syndrome: a comparative study.

OBJECTIVES: Hughes-Stovin syndrome (HSS) is a rare inflammatory condition defined as pulmonary artery aneurysms (PAA) associated with deep vein thrombosis. It is similar to vascular involvement of Behçet's syndrome (BS), but differs in the absence of typical skin-mucosal findings. Whether HSS is a distinct entity or a form fruste of BS is debated. We formally compared HSS cases retrieved from the literature to BS patients with PAI followed by a tertiary centre. METHODS: A systemic literature search using 'Hughes Stovin syndrome' as the key word covering the period between 2000 and 2023 revealed 58 (43 M/15 F) case reports (PROSPERO: CRD42023413537). We identified 74 (62M/12 F) BS patients with PAI followed up in a tertiary centre in Turkey from 2000 until 2020. We evaluated two cohorts head-to-head in terms of demographic and clinical features. RESULTS: BS and HSS patients were found to be comparable with regard to several demographic, clinical and histopathological features. However, PAA were significantly more frequent and isolated pulmonary artery thrombosis (PAT) less common in HSS than that found in BS. Moreover, patients with HSS were more likely to be treated with anti-coagulants and vascular or surgical interventions, whereas less likely to receive immunosuppressive treatment. CONCLUSIONS: Our study indicates that HSS is indeed an 'incomplete form of BS'. It can be considered as evidence supporting the notion that the vascular phenotype develops independently from skin-mucosa lesions and uveitis in BS. However, HSS has been described mainly focusing on aneurysms, overlooking the aspect of in-situ thrombosis.

HLA-B gene methylation and expression in Behçet's syndrome: a potential role of epigenetics in the pathogenesis.

OBJECTIVES: The HLA-B51 locus has the strongest association with Behçet's syndrome (BS). The presence of a CpG island in the HLA-B gene led us to examine the role of epigenetic regulation in BS. METHODS: HLA-B51 genotyping was performed via sequence-specific PCR in 15 index familial BS cases, 17 affected relatives, 26 unaffected relatives, 46 sporadic BS cases, and 41 healthy controls. HLA-B methylation level was determined using the Zymo OneStep qMethyl kit, and HLA-B51 mRNA level was assessed by quantitative real-time PCR in 14 index familial BS cases, 15 affected relatives, 15 unaffected relatives, 11 sporadic BS cases, and 10 healthy controls. RESULTS: HLA-B51 carrier ratio was 13/15 in index familial cases, 13/17 in affected relatives, 22/26 in unaffected relatives, 8/25 in healthy controls, and 35/47 in sporadic BS cases. HLA-B51 expression level in HLA-B51+ BS cases was 2.2-fold higher than in their unaffected relatives (p=0.0149) and 1.3-fold higher than in healthy controls (p=0.0188), while sporadic BS cases had a 2.7-fold higher level than healthy controls (p=0.0487). HLA-B promoter methylation was significantly lower in HLA-B51+ familial BS cases than in unaffected relatives (0.4-fold, p=0.01), affected relatives (0.36-fold, p=0.0219), and healthy controls (0.34-fold, p=0.0371) and slightly lower in HLA-B51+ sporadic BS cases than in healthy controls (0.71-fold, p=0.2347). There was an inverse correlation between HLA-B promoter methylation and HLA-B51 expression in HLA-B51+ sporadic BS cases (p=0.0164). CONCLUSIONS: This study indicates epigenetic involvement associated with the HLA-B51 locus in BS, both in familial and sporadic cases. Further studies with larger sample sizes are needed to confirm our results.

Disease and Treatment-Specific Complications of Behçet Syndrome.

PURPOSE OF REVIEW: We aimed to highlight disease-related and treatment-related complications of Behçet syndrome (BS) based on previous and recent studies and our own experience. RECENT FINDINGS: The Behçet's Disease Overall Damage Index is a newly developed instrument to assess damage in BS. Validation studies showed that damage is already present in some patients at diagnosis and continues to progress during the follow-up, mainly related to treatment complications. Nervous system and eye involvement are important causes of long-term disability. Cyclophosphamide seems to be associated with infertility and an increased risk of malignancies among BS patients, prompting the consideration of shortening the treatment duration. Flares in mucocutaneous manifestations have been reported with tocilizumab, and de novo BS manifestations with secukinumab therapy. Earlier diagnosis and treatment are essential to prevent disease-related damage in BS. Treatment-related complications seem to be the leading cause of damage during the disease course.

Infliximab for vascular involvement in Behçet's syndrome.

OBJECTIVE: Vascular involvement is an important cause of morbidity and mortality in patients with Behçet's syndrome (BS). We aimed to survey the efficacy and safety of infliximab (IFX) in BS patients with vascular involvement followed in a dedicated tertiary center. METHODS: Charts of all BS patients who used IFX for vascular involvement between 2004 and 2022 were reviewed. Primary endpoint was remission at Month 6, defined as lack of new clinical symptoms and findings associated with vascular lesion, lack of worsening of the primary vascular lesion and a new vascular lesion on imaging, and CRP < 10 mg/L. Relapse was defined as development of a new vascular lesion or recurrence of the preexisting vascular lesion. RESULTS: Among the 127 patients (102 men, mean age at IFX initiation: 35.8 ± 9.0 years) treated with IFX, 110 (87%) had received IFX for remission induction and 87 of these (79%) were already on immunosuppressives when the vascular lesion requiring IFX developed. The remission rate was 73% (93/127) at Month 6 and 63% (80/127) at Month 12. Seventeen patients experienced relapses. Remission rates were better among patients with pulmonary artery involvement and venous thrombosis compared to patients with non-pulmonary artery involvement and venous ulcers. Fourteen patients had adverse events leading to IFX discontinuation and 4 had died due to lung adenocarcinoma, sepsis, and pulmonary hypertension-related right heart failure due to pulmonary artery thrombosis (n = 2). CONCLUSION: Infliximab seems to be effective in majority of BS patients with vascular involvement, even in those who are refractory to immunosuppressives and glucocorticoids.

Behçet's disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity.

OBJECTIVES: The endoplasmic reticulum aminopeptidase (ERAP1) haplotype Hap10 encodes for a variant allotype of the endoplasmic reticulum (ER)-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity. This haplotype recessively confers the highest risk for Behçet's diseases (BD) currently known, but only in carriers of HLA-B*51, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact. METHODS: We genotyped and immune phenotyped a cohort of 26 untreated Turkish BD subjects and 22 healthy donors, generated CRISPR-Cas9 ERAP1 KOs from HLA-B*51 + LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems. RESULTS: Allele frequencies of ERAP1-Hap10 were similar to previous studies. There were frequency shifts between antigen-experienced and naïve CD8 T cell populations of carriers and non-carriers of ERAP1-Hap10 in an HLA-B*51 background. ERAP1 KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells. CONCLUSIONS: We demonstrate that hypoactive ERAP1 changes immunogenicity to CD8 T cells, mediated by an HLA class I peptidome with undertrimmed peptides. Naïve/effector CD8 T cell shifts in affected carriers provide evidence of the biological relevance of ERAP1-Hap10/HLA-B*51 at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.

Frequency of AA amyloidosis has decreased in Behçet's syndrome: a retrospective study with long-term follow-up and a systematic review.

OBJECTIVE: A decline in the frequency of AA amyloidosis secondary to RA and infectious diseases has been reported. We aimed to determine the change in the frequency of AA amyloidosis in our Behçet's syndrome (BS) patients and to summarize the clinical characteristics of and outcomes for our patients, and also those identified by a systematic review. METHODS: We identified patients with amyloidosis in our BS cohort (as well as their clinical and laboratory features, treatment, and outcome) through a chart review. The primary end points were end-stage renal disease and death. The prevalence of AA amyloidosis was estimated separately for patients registered during 1976-2000 and those registered during 2001-2017, in order to determine whether there was any change in the frequency. We searched PubMed and EMBASE for reports on BS patients with AA amyloidosis. Risk of bias was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. RESULTS: The prevalence of AA amyloidosis was 0.62% (24/3820) in the earlier cohort and declined to 0.054% (3/5590) in the recent cohort. The systematic review revealed 82 cases in 42 publications. The main features of patients were male predominance and a high frequency of vascular involvement. One-third of patients died within 6 months after diagnosis of amyloidosis. CONCLUSION: The frequency of AA amyloidosis has decreased in patients with BS, which is similar to the decrease observed for AA amyloidosis due to other inflammatory and infectious causes. However, AA amyloidosis is a rare, but potentially fatal complication of BS.

Emergence of new manifestations during infliximab treatment in Behçet's syndrome.

OBJECTIVES: Infliximab (IFX) is increasingly being used for the treatment of severe manifestations of Behçet's syndrome (BS). However, emergence of new manifestations has also been occasionally reported during IFX treatment. We aimed to assess the frequency of new manifestations in our BS patients treated with IFX. METHODS: A chart review was conducted to identify all BS patients treated with IFX in our clinic between 2004 and 2020. Demographic data, indications for IFX initiation, concomitant treatments and outcomes were recorded. A new manifestation was defined as the emergence of a new organ involvement or mucocutaneous manifestation developing for the first time during IFX treatment or within 12 weeks after the last infusion of IFX. RESULTS: Among our 282 patients who used IFX, 19 (7%) patients had developed a total of 23 new manifestations during a mean follow-up of 20.0 (15.3) months. Patients with vascular involvement were more likely to develop a new manifestation (12/19, 63%). Initial manifestations that required IFX were in remission at the time of new manifestation in 14/19 patients. IFX treatment was intensified (n = 6) and/or glucocorticoids, immunosuppressives or colchicine was added to IFX (n = 21). IFX was switched to another agent for the remaining manifestations (n = 8). These treatment modifications led to remission in 17/19 patients. CONCLUSION: New manifestations developed during IFX treatment in 7% of our patients with BS. They could be managed by intensifying IFX treatment or adding other agents in the majority of these manifestations.

Screening for latent tuberculosis before starting TNF-alpha inhibitors in a population with high BCG vaccination rates.

It is assumed that in candidates for TNF-alpha inhibitor (TNFi) treatment, tuberculin skin test (TST) may be unreliable, since BCG vaccination causes false positive and drugs cause false negative results, favoring the use of Quantiferon or T-spot assays. However, these tests may not be readily available in all parts of the world. We aimed to determine the reliability of TST with respect to BCG vaccination and drugs in candidates for TNFi treatment, and how isoniazid is tolerated, assuming that the use of TST would result in increased isoniazid use. We included 1031 adult patients who were prescribed a TNFi for the first time. We analysed the association of BCG and drugs with TST and Quantiferon results, the determinants of a positive TST, and evaluated the tolerability of isoniazid. BCG vaccination and male sex were associated with positive TST (OR 3.56, 95% CI 1.98-6.41 and OR 2.54, 95% CI 1.75-3.68, respectively), while prednisolone and azathioprine were associated with negative TST (OR 0.63, 95% CI 0.43-0.91 and OR 0.40, 95% CI 0.11-0.76). Isoniazid was prescribed to 684 (66.3%) patients and had to be discontinued in 12.2% of these before 9 months, most commonly due to hepatotoxicity (44%). One patient developed tuberculosis despite isoniazid use. BCG vaccination may be associated with false positive TST, despite a long time since vaccination in candidates for TNFi treatment. Prednisolone and azathioprine use were associated with negative TST. Despite the high frequency of isoniazid use associated with using TST instead of QTF, isoniazid was generally well tolerated.

The incidence, clinical characteristics, and outcome of COVID-19 in a prospectively followed cohort of patients with Behçet's syndrome.

Initial case series of small number of patients at the beginning of the pandemic reported a rather guarded prognosis for Behçet's syndrome (BS) patients infected with SARS-CoV-2. In this prospective study, we describe the incidence, clinical characteristics, disease course, management, and outcome in a large cohort of BS patients with laboratory-confirmed infection of SARS-CoV-2. We defined a cohort of 1047 registered BS patients who were aged between 16 and 60 years and seen routinely before the pandemic at the multidisciplinary outpatient clinic. We followed prospectively this cohort from beginning of April 2020 until the end of April 2021. During 13 months of follow-up, of the 1047 (599 M/448 F) patients, 592 (56.5%) were tested for SARS-CoV-2 PCR at least once and 215 (20.5%; 95% CI 0.18-0.23) were tested positive. We observed 2 peaks which took place in December 2020 and April 2021. Of the 215 PCR positive patients, complete information was available in 214. Of these 214, 14 (6.5%) were asymptomatic for COVID-19. In the remaining, the most common symptoms were anosmia, fatigue, fever, arthralgia, and headache. A total of 40 (18.7%) had lung involvement, 25 (11.7%) were hospitalized, 1 was admitted to the intensive care unit while none died. Favipiravir was the most prescribed drug (74.3%), followed by colchicine (40.2%), and hydroxychloroquine (20.1%) in the treatment of COVID-19. After COVID-19, 5 patients (2.3%) were given supplemental O2 and 31 (14.5%) antiaggregant or anticoagulants. During COVID-19, of the 214 PCR positive patients, 116 (54.2%) decreased the dose of their immunosuppressives or stopped taking completely; 36 (16.8%) experienced a BS flare which was mostly oral ulcers (10.3%). None of the patients reported a thrombotic event. A total of 93 (43.5%) patients reported BS flares after a median 45 days of COVID-19 infection and this was found to be significantly associated with immunosuppressive drug discontinuation. Multiple regression analysis adjusted for age and gender indicated that smoking and using interferon-alpha decreased the likelihood of getting COVID-19. The incidence and severity of COVID-19 did not differ between those who were using colchicine or not. The cumulative incidence of COVID-19 in this prospectively followed cohort of BS patients was almost two folds of that estimated for the general population living in Istanbul, Turkey, however, the clinical outcome of COVID-19 was not severe and there was no mortality. The protective effect of smoking and interferon deserves further investigation. On the other hand, colchicine did not have any positive or negative effect against COVID-19. Significant number of patients flared after COVID-19, however, this was significantly associated with immunosuppressive discontinuation during the infection. Contrary to our previous observations, COVID-19 did not seem to exacerbate thrombotic events during or after the infection.

Clinical course of acute deep vein thrombosis of the legs in Behçet's syndrome.

OBJECTIVES: Lower extremity deep vein thrombosis (LEDVT) is a serious complication of Behçet's syndrome. Management constitutes mainly of administration of immunosuppressives, but the predictors of relapse and the optimal choice of immunosuppressives remain unclear. In this prospective study, we aimed to detect the risk and predictors of relapse and treatment response to different modalities. METHODS: All Behçet's syndrome patients who presented with a first episode of acute LEDVT between 2010 and 2014 were prospectively followed with a standard protocol. Acute LEDVT was confirmed by Doppler ultrasonography. Serial planned Doppler ultrasonography assessments were performed during follow-up and additionally repeated in case of clinical suspicion. Recanalization rate was assessed at each visit. Our first-line treatment strategy consisted of AZA and CSs. IFN-alpha was used in patients who were refractory to or could not tolerate AZA or had concomitant eye involvement requiring further treatment. RESULTS: Thirty-three patients with LEDVT (26 M/7 F) were prospectively followed for 40.7 ± 13.4 months. Among the 33 patients, 23 relapses were observed in 15 patients. Relapse rates were 29%, 37% and 45% at 6, 12 and 24 months, respectively. Among the possible predictors of relapse, poor recanalization was the only significant factor [hazard ratio 4.34 (95% CI 1.96, 10.0)]. Overall 29 patients were treated with AZA and 17 with IFN-alpha. The relapse rate was lower and recanalization rate was higher with IFN-alpha compared with AZA (12% vs 45% and 86% vs 45%). CONCLUSION: The relapse rate for LEDVT in Behçet's syndrome is high despite AZA treatment. IFN-alpha seems to be a promising agent for preventing LEDVT relapses and achieving good recanalization.

Peripheral blood mononuclear cell proteome profile in Behçet's syndrome.

Behçet's syndrome (BS) is a systemic inflammatory disorder with unknown etiology. Investigation of proteome profiles of disease specific cells facilitates our understanding of the processes and related molecular pathways, especially in disorders like BS with complex inheritance pattern and clinical heterogeneity. In the current study, we evaluated the peripheral blood mononuclear cells (PBMCs) proteome of 59 patients with BS (33 in active and 26 in inactive phases) and of 28 healthy controls using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Differentially expressed protein spots with at least twofold and/or statistically significant change (p ≤ 0.05) between active BS vs inactive BS, and also active BS vs healthy controls were identified by mass spectrometry (MALDI-TOF/TOF). Bioinformatic analyses revealed 16 differentially expressed proteins (12 of them in active vs inactive BS comparison, whereas 11 of them for active BS vs healthy control comparison) belonging to glycolysis, cytoskeleton organization, protein folding, and regulation of blood coagulation pathways. Stathmin (active BS vs inactive BS; fourfold, active BS vs healthy control; 4.7-fold) and WD repeat-containing protein-1 (active BS vs inactive BS; 2.7-fold, active BS vs healthy control; 2.7-fold), which are cytoskeleton-related proteins, were found to be lower in active patients compared to inactive patients and healthy control. Decreased levels of calreticulin (active BS vs inactive BS; 1.29-fold) and heat shock 70 kDa protein 8 (active BS vs healthy control; 1.5-fold) which are involved in protein folding and endoplasmic reticulum (ER) stress process, were observed in patients with active phase of BS. Down-regulation of protein folding and ER stress process proteins in BS patients may further support the involvement of ER stress in BS.

Patients' experiences with Behçet's syndrome: structured interviews among patients with different types of organ involvement.

OBJECTIVES: Behçet's syndrome (BS) is a multisystem variable-vessel vasculitis with significant life impact. The aim of this study was to explore the perspectives of patients with BS with different types of organ involvement. METHODS: Semi-structured qualitative interviews were conducted with 20 patients with BS with different types of organ involvement. Interviews were audio-recorded, transcribed, and translated into English. A Grounded Theory approach was employed in thematic analysis of translated interviews. RESULTS: Interviews with participants yielded four themes, including symptoms (skin problems, pain, vision problems, fatigue/sleep disturbances, and gastrointestinal/weight loss), impact on function (impact on speech and vision, mobility, energy for tasks, adaptations, and self-care), psychological impact (emotions and emotional management techniques), and social impact (ability to socialize generally and impact on familial relationships). CONCLUSIONS: Patients with BS identified several domains, including physical functioning, psychological state, and social identity that are significantly modulated by the symptoms of BS. Those are inter-related with physical symptoms, reflecting the multi-system character of BS, and impair patients' function impacting on psychological and social identities. This work advances an understanding of BS, and will be useful in developing patient-oriented outcome measures for use in studying BS.

Biosimilar infliximab for Behçet's syndrome: a case series.

OBJECTIVES: The efficacy and safety of biosimilar infliximab (bio-IFX) was shown in randomised controlled trials and it was approved for all indications of the reference product in several countries. However, a previous case series of 3 patients with Behçet's syndrome (BS) reported disappointing results. We aimed to share our experience with bio-IFX treatment in different types of organ involvement in patients with BS. METHODS: We reviewed the charts of all BS patients who were prescribed reference infliximab (ref-IFX) or bio-IFX in our BS clinic. Among the 181 BS patients who were prescribed IFX since 2003, 6 (3%) were prescribed bio-IFX due to refractory disease despite conventional immunosuppressives. RESULTS: A total of 6 patients (mean age: 32.1±6.2, mean disease duration: 5.3±1.8 years, 5 men and 1 woman) received bio-IFX for uveitis, nervous system, vascular and joint involvement. Four of the 6 patients obtained remission and stayed in remission during the 16±6.5 months they used bio-IFX. Among the 4 patients who obtained remission, 2 were switched to ref-IFX due to unavailability of bio-IFX infusion set and did not experience adverse events or loss of efficacy. However, relapses occurred during tapering. The other 2 patients are still in remission with bio- IFX. Among the remaining 2 patients, one had to be switched to ref-IFX after the first infusion, due to a change in the reimbursement policy and the other was non-responsive. CONCLUSIONS: Our limited experience showed that bio-IFX may be a safe and effective alternative for patients with BS, refractory to conventional immunosuppressives.

2018 update of the EULAR recommendations for the management of Behçet's syndrome.

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.

Management of major organ involvement of Behçet's syndrome: a systematic review for update of the EULAR recommendations.

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.

Myelopathy in Behçet's disease: The Bagel Sign.

OBJECTIVE: To describe the clinical and distinctive imaging features of myelopathy associated with Behçet's disease (BD). METHODS: We evaluated the records of patients meeting the following criteria: (1) fulfillment of the International Study Group criteria for BD; (2) clinically suggestive of myelopathy; (3) simultaneous spinal cord and brain magnetic resonance images (MRIs) within 1 month of acute worsening of myelopathy; and (4) follow-up duration ≥ 1 year after initial MRI evaluation. Patients not fulfilling all inclusion criteria and having MRIs with poor quality or missing sequences were excluded. RESULTS: In 11 patients (9 men, 2 women), we studied 14 MRIs during distinct myelopathy episodes and nine follow-up MRIs. Two distinct MRI patterns of spinal cord involvement were described according to T2-weighted (T2W) axial images: (1) "Bagel Sign" pattern: a central lesion with hypointense core and hyperintense rim with or without contrast enhancement; and (2) "Motor Neuron" pattern: a symmetric involvement of the anterior horn cells. Bagel Sign was present in 13 of 14 myelopathy episodes whereas Motor Neuron pattern was observed in 1 of 14 MRIs. Of the 13 MRIs with Bagel Sign long myelopathy (n = 9), both long and short myelopathy (n = 2) and short myelopathy (n = 2) was observed. All patterns cleared with some residual lesions after steroid use and immunomodulation with associated clinical recovery in patients. INTERPRETATION: The signal characteristics of the Bagel Sign potentially represent venous engorgement and/or acute blood products within the spinal cord. To our knowledge, Bagel Sign has not been observed in other forms of longitudinal myelopathy outside of BD, including neuromyelitis optica. Ann Neurol 2017;82:288-298.

Faecal but not serum calprotectin levels look promising in predicting active disease in Behçet's syndrome patients with gastrointestinal involvement.

OBJECTIVES: The faecal calprotectin (FC) test is widely used as a non-invasive method for identifying intestinal inflammation. A recent study suggested FC may help to diagnose gastrointestinal involvement of Behçet's syndrome (GIBS). We aimed to determine whether FC helps to distinguish active from inactive intestinal involvement in GIBS. METHODS: We tried to contact 70 GIBS patients registered in our tertiary multidisciplinary clinic. We prospectively collected faecal specimens and serum from 39 GIBS patients who gave informed consent assessing calprotectin and CRP levels followed by a colonoscopy. We included 47 Crohn's disease (CD) patients as controls. Active disease was defined as having ulcer/s on colonoscopy. We filled the Disease Activity Index for Intestinal Behçet's Disease (DAIBD) and Crohn's Disease Activity Index (CDAI). The cut-off for positive FC was defined as ≥150 µg/g. RESULTS: Ulcers were detected in 12/39 GIBS patients. Sensitivity and specificity of the FC test for active disease was 91.7 (95%CI:61.5-99.8) and 74.1% (95%CI:53.7-88.9). Median FC and CRP levels and DAIBD scores were higher among patients with ulcers, whereas serum calprotectin and CDAI scores were not. A negative FC test was the only significant predictor of remission (OR:37.04, 95%CI:2.4-561.6; p=0.009) on multivariate analysis. Among CD patients, 16/25 active patients and 3/22 patients in endoscopic remission had a positive FC test (OR:11, 95%CI:11-49). CONCLUSIONS: FC, but not serum calprotectin seems to be a useful non-invasive tool for assessing disease activity in GIBS. Whether the presence of oral ulcers can cause false positive results remains to be studied.