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Sinem Nihal Esatoglu,1 Zekayi Kutlubay,2 Didar Ucar,3 Ibrahim Hatemi,4 Ugur Uygunoglu,5 Aksel Siva,5 Gulen Hatemi1 1Division of Rheumatology, Department of Internal Medicine, 2Department of Dermatology, 3Department of Ophthalmology, 4Division of Gastroenterology, Department of Internal Medicine 5Department of Neurology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey Abstract: Behçet’s syndrome (BS) is a multisystem vasculitis that presents with a variety of mucocutaneous manifestations such as oral and genital ulcers, papulopustular lesions and erythema nodosum as well as ocular, vascular, gastrointestinal and nervous system involvement. Although it occurs worldwide, it is especially prevalent in the Far East and around the Mediterranean Sea. Male gender and younger age at disease onset are associated with a more severe disease course. The management of BS depends on the severity of symptoms. If untreated, morbidity and mortality are considerably high in patients with major organ involvement. Multidisciplinary patient care is essential for the management of BS, as it is for other multisystem diseases. Rheumatologists, dermatologists, ophthalmologists, neurologists, cardiovascular surgeons and gastroenterologists are members of the multidisciplinary team. In this study, we reviewed the epidemiology, etiology, diagnostic criteria sets, clinical findings and treatment of BS and highlighted the importance of the multidisciplinary team in the management of BS. Keywords: Behçet disease, multidisciplinary care, diagnosis, treatment, vasculitis, epidemiology, management

Objectives: Tocilizumab has been increasingly reported as an alternative therapeutic agent in the management of Behçet's syndrome (BS) and it has been mostly tried in BS patients with neurological and eye involvement. As therapeutic responses to each drug may vary across different types of BS involvement, we aimed to report seven patients with large vessel involvement treated with tocilizumab., Methods: We enrolled seven BS patients with vascular involvement who were given tocilizumab at the Behçet's Disease Research Centre in Istanbul University-Cerrahpaşa between 2000 and 2022. Demographic information, BS features, types of vascular involvement, previous and concomitant medications, C-reactive protein (CRP) levels, imaging modality results, and outcomes were documented from the patients' medical records., Results: Within a median of 6 months after the initiation of tocilizumab, 5 patients experienced vascular relapses. These relapses included the emergence of new bilateral pulmonary artery aneurysms, a new pulmonary artery thrombus, parenchymal lung involvement, deep vein thrombosis in the lower extremity, and pseudotumor cerebri in one patient each. CRP levels were normal in 4 of the 5 patients at the time of vascular relapse. One of these 5 patients and another patient with aortitis had an exacerbation of mucocutaneous symptoms. In the last patient, venous ulcers did not respond to tocilizumab and were complicated with infection., Conclusions: Tocilizumab could potentially exacerbate vascular manifestations, similar to what is observed with mucocutaneous lesions in BS patients. Furthermore, CRP levels appear to be ineffective in monitoring these patients.

Objectives: Treatment response may be variable across organ manifestations of Behçet syndrome (BS). We aimed to determine the frequency of de novo manifestations during adalimumab treatment., Methods: We conducted a chart review of all BS patients who received adalimumab in our center between 2008 and 2023. Demographic data, reasons for initiating adalimumab, concurrent medications, previous treatments, and outcomes were recorded. We defined de novo manifestations as new BS manifestations that occurred for the first time during treatment with adalimumab. For patients with vascular involvement, a new vascular event at another vessel was also considered as a de novo manifestation., Results: Among the 335 patients, a de novo manifestation developed in 14 (4%) patients. De novo manifestations were vascular involvement in 5 patients, arthritis in 3, anterior uveitis in 2, nervous system involvement in 2, gastrointestinal involvement in 1, and epididymitis in 1 patient. The primary reasons for adalimumab treatment were vascular involvement in 5 patients, uveitis in 4, arthritis in 3, mucocutaneous involvement in 1, and epididymitis in 1 patient. Upon the development of de novo manifestation, adalimumab was switched to another biologic in 4 patients, dose was intensified in 3, colchicine, conventional immunosuppressives, and/or glucocorticoids were added in 5, and topical eye drops were added in 2 patients, leading to remission of de novo manifestations in all patients., Conclusion: De novo manifestations were infrequent (4%) among BS patients treated with adalimumab. Of these, 57% were major organ involvement, mainly vascular involvement. None of the patients developed posterior uveitis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The prognostic importance of vitreous cells (VC) in patients with Behçet syndrome (BS) is unknown. We aimed to determine the frequency of developing posterior uveitis (PU) and any additional risk factors associated with the development of PU in BS patients with VC at diagnosis., Methods: The charts of 572 consecutive BS patients who were registered between 2010 and 2012 were reviewed. Among the patients with a follow-up of ≥2 years, we included 110 patients with VC in one or both eyes and 147 patients without any eye findings in both eyes at baseline and compared them for the development of PU., Results: Among the 110 included patients with VC, 61 had VC in both eyes, 34 had VC in only one eye, and 15 had VC in one eye and PU in the other eye. There was anterior uveitis (AU) in addition to VC in the same eye in 13 patients at baseline. PU developed in 24 (22%) of these patients during a mean follow-up of 1.9 ± 1.1 years. This was significantly more frequent than the 147 patients without any eye findings at baseline, among whom there were only 2 patients who developed PU ( p  < 0.001). Multivariate logistic regression analysis showed that having AU in addition to VC in the same eye (OR, 5.03, 95% CI; 1.37-18.47) was an independent risk factor for the development of PU in patients with VC., Conclusion: Careful follow-up is required for patients with VC at diagnosis, since 22% developed PU within 2 years.

Introduction/objective: There is currently no tool available to assess the severity of damage in uveitis due to Behçet's syndrome (BS). In this preliminary study, we developed a new grading system to evaluate ocular damage and assessed it in a prospective cohort., Methods: A specialist in BS uveitis (YO) developed a grading system for ocular damage with five grades based on the extent of damage in the posterior segment. YO trained a senior and general ophthalmologist with sample fundus images. BS patients who had undergone color fundus photography during their routine visits in attack-free periods were included in the study. The color fundus photos of this prospective cohort were evaluated blindly by YO and his trainees using the new grading tool. Inter and intra-observer agreement between the graders were assessed by Cohen's kappa analysis. The evaluation of YO was considered as the gold standard., Results: One hundred eighty-five eyes of 108 (29 F/79 M) patients with BS uveitis were graded for damage by two investigators. Their mean age was 38,58 years and their median ocular disease duration was 13 years. The gold standard and the two investigators exhibited substantial concordance with the ocular damage grading system. The inter- and intra-observer agreement were also almost perfect., Conclusion: The newly developed ocular damage grading system enables the standardization of damage severity in BS uveitis. It is imperative to conduct internal and external validations across diverse cohorts. Furthermore, future studies should investigate its correlation with other multimodal imaging methods such as fluorescein angiography and optical coherence tomography.

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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The evidence for the treatment of connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) mostly depends on subgroup or post hoc analysis of randomized controlled trials (RCTs). Thus, we performed a meta-analysis of RCTs that reported outcomes for CTD-PAH. PubMed and EMBASE were searched for CTD-PAH treatment. The selected outcomes were functional class (FC) change, survival rates, 6-min walk distance (6-MWD), clinical worsening (CW), N-terminal prohormone BNP (NT-proBNP), pulmonary vascular resistance (PVR), mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), and cardiac index (CI). The meta-analysis was conducted according to the PRISMA guidelines and registered in PROSPERO (CRD42020153560). Twelve RCTs conducted with 1837 patients were included. The diagnoses were systemic sclerosis in 59%, SLE in 20%, and other CTDs in 21%. The pharmacological interventions were epoprostenol, treprostinil, sildenafil, tadalafil, bosentan, macitentan, ambrisentan, riociguat, and selexipag. There was a significant difference between interventions and placebo in FC, 6MWD, CW, PVR, RAP, and CI that favored intervention. Our analysis showed a 39% reduction in the CW risk with PAH treatment. The short-term survival rates and mean serum NT-proBNP changes were similar between the study and control groups. Treatment for CTD-PAH had favorable effects on clinical and hemodynamic outcomes but not on survival and NT-proBNP levels. Different from the previous meta-analyses that focused on 6-MWD, time to clinical worsening, and CW as outcomes, this meta-analysis additionally reports the pooled analysis of change in FC, hemodynamic measurements (RAP, PVR, CI), and NT-proBNP, some of which have prognostic value for PAH., (© 2024. The Author(s).)

Objectives: Neurosensory hearing loss is well-documented in chronic autoimmune conditions such as systemic lupus erythematosus (SLE). However, the literature lacks data on the prevalence and characteristics of hearing impairment in Takayasu's arteritis (TAK). In this cross-sectional study, our principal objective was to systematically assess the auditory function of individuals diagnosed with TAK, against SLE patients and healthy controls (HC)., Methods: Age and gender matched TAK and SLE patients followed up in a tertiary centre along with healthy controls were included in a two-phase study. In the first phase, a questionnaire on ENT symptoms was administered to the patient (TAK: n=104 and SLE: n= 151) and HC (n=174) groups. In the second phase, patients (TAK: n=53 and SLE: n=33) and HC (n=45) underwent audiometric tests., Results: The questionnaire survey revealed that both TAK and SLE patients reported hearing loss (27.9%, 25.8%, 7.4%, p<0.001), tinnitus (49%, 35.8%, 13.8%, p<0.001) and vertigo (46.2%, 33.8%, 16.7%, p<0.001) at significantly higher rates than HC. Audiometry results indicated that both TAK (30.2%) and SLE patients (18.2%) had increased hearing loss compared to HC (8.9%), however, only TAK patients were found to have significantly increased risk in age adjusted logistic regression analysis (OR= 3.915, 95%CI: 1.179-12.998, p=0.026). Hearing loss was mainly neurosensory in all groups. TAK patients were affected at both low (<6000 Hz) and high (>6000 Hz) frequencies, whereas SLE patients were affected only at high frequencies. Hearing loss was significantly associated only with older age. No association was observed with the anatomical location of vascular involvement or history of stroke., Conclusions: Our study reveals an increased prevalence of hearing loss in TAK. Further research is crucial to uncover the underlying causes.

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Experience with mycophenolate in uveitis due to Behçet syndrome (BS) is limited. Twelve patients with panuveitis or posterior uveitis who were started mycophenolate were included. Data on demographic characteristics, therapies, ocular attacks, and adverse events were extracted from patient charts. Seven patients with BS uveitis were prescribed mycophenolate for remission induction, of which 6 were refractory/intolerant to conventional immunosuppressives. Mycophenolate was combined with anti-TNFs in 3 patients, resulting in no further ocular attacks. Mycophenolate had to be stopped in the fourth patient due to adverse events. The remaining 3 patients continued to have ocular attacks and were switched to other agents without any drop in visual acuity. Among the 5 patients who were prescribed mycophenolate for maintenance, 2 were relapse free, but 3 experienced ocular attacks. One patient had an exacerbation of mucocutaneous lesions, and 2 experienced adverse events. Mycophenolate monotherapy may not be adequate for remission induction of refractory BS uveitis, but it can be a safe and effective alternative when combined with a biologic agent. It may also be an option for maintenance therapy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Prof Hatemi has received research grant, lecture fees and fees for serving on an advisory board from Celgene, received consulting fees from UCB Pharma, Bayer, Johnson & Johnson, lecture fees from Novartis, Abbvie, Amgen, and UCB Pharma. Yesim Ozguler has received honorariums for presentations from UCB Pharma, Novartis, and Pfizer. Ugur Uygunoglu has received advisory board honorariums and speaker fees from F Hoffmann La-Roche, Bayer, Merck-Serono, Novartis, Teva, and Biogen Idec/Gen Pharma of Turkey. Aksel Siva received honorariums from Bayer-Schering AG, Biogen/Gen Ilac of Turkey, Genzyme, Merck-Serono, and Roche for consulting, fees from Novartis as a consultant and advisory committee member, travel and registration reimbursements from Genzyme, and honorariums from Teva for speaking engagements. Prof Hamuryudan has received consultation fees from Abbvie, Novartis, Pfizer, and Roche. No other disclosures were reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Systemic sclerosis (SSc) represents extremely rare disease with majority of data coming from adults. Studies comparing juvenile- (jSSc) and adult-onset (aSSc) patients are limited. We aimed to compare clinical features, treatment modalities and survival rates of jSSc and aSSc patients., Methods: A retrospective study among pediatric and adult Scl patients has been performed. Demographic characteristics, clinical features, autoantibody profiles, and treatment data were retrieved from the databases. Survival analysis was done using Kaplan-Meier plot and factors associated with mortality were identified with multiple regression analysis., Results: A total of 158 adults and 58 juvenile Scl patients were identified. The mean age at the disease onset was 37±14.7 vs. 8.8 ± 4.1 years, mean age at diagnosis 42±15.2 vs. 10.4 ± 3.8 years and mean follow-up duration was 6.3 ± 4.9 years vs. 6.6 ± 4.9 years for aSSc and jSSc patients, respectively. The frequency of interstitial lung disease (ILD) (50.9% vs 30%, p<0.001) and systemic hypertension (17.9% vs 0, p = 0.009) was significantly higher among aSSc. While aSSc patients had presented mostly with limited cutaneous subset (74.1%), diffuse cutaneous subset was the dominant subset among jSSc (76.7%), (p<0.001). The mortality rate was significantly higher among adults (p = 0.005). The ILD (p = 0.03) and cardiac insufficiency (p = 0.05) were independent risk factors of mortality in both aSSc and jSSc patients., Conclusion: Juvenile and adult-onset Scl represent rarely seen conditions with different clinical phenotypes. Pediatric patients with LS are more commonly seen by pediatric rheumatologists, in contrary to adults. Diffuse disease subset is the dominant form among juvenile patients, whereas limited form is the main disease subset among adults. On the other hand, juvenile-onset patients have a better survival than those with adult-onset., Competing Interests: Declaration of Competing Interest Sinem Nihal Esatoglu has received honorariums for presentations from UCB Pharma, Roche, Pfizer, and Merck Sharp Dohme. Gulen Hatemi has received grant/research support from Celgene and has served as a speaker for AbbVie, Celgene, Novartis, and UCB Pharma. Emire Seyahi has received honorariums for presentations from Novartis, Pfizer, and AbbVie. No other disclosures were reported., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Behçet's syndrome (BS) has a heterogeneous clinical phenotype, and its clinical manifestations may respond differently to drugs commonly used to treat BS. The type, dose, and duration of immunomodulatory, immunosuppressive, and biologic agents should be tailored individually., Areas Covered: We reviewed the literature for articles on BS management that were published until June 2022 and summarized the management options in BS for each type of organ involvement. We aimed to cover all currently available pharmacological agents used in BS, as well as surgical and interventional options, focusing on recent evidence., Expert Opinion: The management aims in BS are to preserve function and quality of life and to avoid damage. The choice of treatment modalities depends on the organs that are actively involved, the severity of that involvement, and prognostic factors. A treat-to-attack strategy would help improve long-term outcomes in BS.

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., (© The Author(s) 2022. 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: 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., (© 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.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose of Review: The purpose of this review is to summarize the recent advances in Takayasu arteritis (TAK), mainly focusing on pathogenesis, imaging modalities, and management., Recent Findings: Three novel clusters based on angiographic findings were identified in the Indian cohort and replicated in the North American cohorts. Different new imaging modalities have been tried in the assessment of arterial inflammation with promising results. There is more evidence on the long-term use of tocilizumab, but relapses are common. In light of the recent findings on the pathogenesis of TAK, Janus kinase inhibitors seem to be promising., Summary: Improvement in imaging modalities and in our understanding of the disease pathogenesis will allow us to better assess the disease activity and identify effective therapeutic agents., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Due to current advances and growing experience in the management of coronavirus Disease 2019 (COVID-19), the outcome of COVID-19 patients with severe/critical illness would be expected to be better in the second wave compared with the first wave. As our hospitalization criteria changed in the second wave, we aimed to investigate whether a favorable outcome occurred in hospitalized COVID-19 patients with only severe/critical illness. Among 642 laboratory-confirmed hospitalized COVID-19 patients in the first wave and 1121 in the second wave, those who met World Health Organization (WHO) definitions for severe or critical illness on admission or during follow-up were surveyed. Data on demographics, comorbidities, C-reactive protein (CRP) levels on admission, and outcomes were obtained from an electronic hospital database. Univariate analysis was performed to compare the characteristics of patients in the first and second waves. There were 228 (35.5%) patients with severe/critical illness in the first wave and 681 (60.7%) in the second wave. Both groups were similar in terms of age, gender, and comorbidities, other than chronic kidney disease. Median serum CRP levels were significantly higher in patients in the second wave compared with those in the first wave [109 mg/L (interquartile range [IQR]: 65-157) vs. 87 mg/L (IQR: 39-140); p < 0.001]. However, intensive care unit admission and mortality rates were similar among the waves. Even though a lower mortality rate in the second wave has been reported in previous studies, including all hospitalized COVID-19 patients, we found similar demographics and outcomes among hospitalized COVID-19 patients with severe/critical illness in the first and second wave., (© 2021 Wiley Periodicals LLC.)

Purpose: There is scarce data on the impact of the presence of mediastinal lymphadenopathy on the prognosis of coronavirus-disease 2019 (COVID-19). We aimed to investigate whether its presence is associated with increased risk for 30-day mortality in a large group of patients with COVID-19., Method: In this retrospective cross-sectional study, 650 adult laboratory-confirmed hospitalized COVID-19 patients were included. Patients with comorbidities that may cause enlarged mediastinal lymphadenopathy were excluded. Demographics, clinical characteristics, vital and laboratory findings, and outcome were obtained from electronic medical records. Computed tomography scans were evaluated by two blinded radiologists. Univariate and multivariate logistic regression analyses were performed to determine independent predictive factors of 30-day mortality., Results: Patients with enlarged mediastinal lymphadenopathy (n = 60, 9.2%) were older and more likely to have at least one comorbidity than patients without enlarged mediastinal lymphadenopathy (p = 0.03, p = 0.003). There were more deaths in patients with enlarged mediastinal lymphadenopathy than in those without (11/60 vs 45/590, p = 0.01). Older age (OR:3.74, 95% CI: 2.06-6.79; p < 0.001), presence of consolidation pattern (OR:1.93, 95% CI: 1.09-3.40; p = 0.02) and enlarged mediastinal lymphadenopathy (OR:2.38, 95% CI:1.13-4.98; p = 0.02) were independently associated with 30-day mortality., Conclusion: In this large group of hospitalized patients with COVID-19, we found that in addition to older age and consolidation pattern on CT scan, enlarged mediastinal lymphadenopathy were independently associated with increased mortality. Mediastinal evaluation should be performed in all patients with COVID-19., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The course of novel coronavirus disease 2019 (COVID-19) has been of special concern in patients with inflammatory rheumatic diseases (IRDs) due to the immune dysregulation that may be associated with these diseases and the medications used for IRDs, that may affect innate immune responses., Objective: In this cohort study, we aimed to report the disease characteristics and variables associated with COVID-19 outcome among Turkish patients with IRDs., Methods: Between April and June, 2020, 167 adult IRD patients with COVID-19 were registered from 31 centers in 14 cities in Turkey. Disease outcome was classified in 4 categories; (i) outpatient management, (ii) hospitalization without oxygen requirement, (iii) hospitalization with oxygen requirement, and (iv) intensive care unit (ICU) admission or death. Multivariable ordinal logistic regression analysis was conducted to determine variables associated with a worse outcome., Results: 165 patients (mean age: 50 ± 15.6 years, 58.2% female) were included. Twenty-four patients (14.5%) recovered under outpatient management, 141 (85.5%) were hospitalized, 49 (30%) required inpatient oxygen support, 22 (13%) were treated in the ICU (17 received invasive mechanic ventilation) and 16 (10%) died. Glucocorticoid use (OR: 4.53, 95%CI 1.65-12.76), chronic kidney disease (OR: 12.8, 95%CI 2.25-103.5), pulmonary disease (OR: 2.66, 95%CI 1.08-6.61) and obesity (OR: 3.7, 95%CI 1.01-13.87) were associated with a worse outcome. Biologic disease-modifying antirheumatic drugs (DMARDs) do not seem to affect COVID-19 outcome while conventional synthetic DMARDs may have a protective effect (OR: 0.36, 95%CI 0.17-0.75). Estimates for the associations between IRD diagnoses and outcome were inconclusive., Conclusions: Among IRD patients with COVID-19, comorbidities and glucocorticoid use were associated with a worse outcome, while biologic DMARDs do not seem to be associated with a worse outcome., Competing Interests: KT has served as a speaker for Gilead. GH has received grant/research support from Celgene and has served as a speaker for AbbVie, Celgene, Novartis, and UCB Pharma. 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 Esatoglu, Tascilar, Babaoğlu, Bes, Yurttas, Akar, Pehlivan, Akleylek, Tecer, Seyahi, Yuce-Inel, Alpay-Kanitez, Bodakci, Tekgoz, Colak, Bolek, Koca, Kalyoncu, Icacan, Ugurlu, Oz, Hamuryudan, Hatemi and the Turkish Society for Rheumatology COVID-19 Registry Investigators.)

Relapsing polychondritis is a systemic inflammatory disease that mainly affects ears, nose, eyes, joints, and large airway. Relapsing polychondritis may also affect cardiac valves and large vessels with the aorta being most frequently involved. We conducted a systematic literature review to delineate the clinical characteristics, treatment, and outcome of relapsing polychondritis patients with aortic involvement including thoracic and abdominal aorta, aortic valve, and coronary arteries. 113 patients reported in 85 manuscripts were retrieved through the systematic literature search and references of the selected manuscripts. With the addition of a patient from our center, a total of 114 patients were included in the analyses. Aortic vessel involvement was the predominant type of involvement that was identified in 93 (82%) patients, while aortic valve involvement was identified in 41 patients (36%). The median age at aortic involvement was 37 years [IQR: 30-53] with a delay of 5 years [IQR: 1-8] between first relapsing polychondritis symptom and aortic involvement. Nineteen percent of the patients were asymptomatic at the time of aortic involvement diagnosis. The initial treatment was immunosuppressives in 41 patients (56%) and surgery in 28 patients (38%). The mortality ratio was 27% in a 24 month follow-up [IQR: 7.5-54 months]. Aortic dissection or rupture was the most frequent causes of mortality. Concomitant coronary artery involvement suggested a worse outcome. Aortic involvement in relapsing polychondritis is a mortal complication despite medical and surgical treatments. It may be asymptomatic in 19% of the patients which warrants the importance of screening.

Background: Immunogenicity of tumor necrosis factor alpha inhibitors (TNFis) has been recognized as an important problem that may cause loss of efficacy and adverse events such as infusion reactions. TNFis are being increasingly used among patients with Behçet syndrome (BS) and scarce data exist on this topic., Objective: We aimed to investigate the prevalence of anti-infliximab (IFX) antibodies in patients with Behçet syndrome together with suitable controls., Methods: We collected serum samples from 66 consecutive Behçet syndrome patients (51 M, 15 F, mean age 37 ± 9 years) who were treated with IFX. Additionally, similarly treated 27 rheumatoid arthritis, 53 ankylosing spondylitis, 25 Crohn's disease patients, and 31 healthy subjects were included as controls. Samples were collected just before an infusion, stored at -80°C until analysis, and serum IFX trough levels and anti-IFX antibodies were measured by ELISA. We used a cut-off value of 1 μg/ml for serum IFX trough level, extrapolating from rheumatoid arthritis studies., Results: Anti-IFX antibodies were detected in four (6%) Behçet syndrome, five (18.5%) rheumatoid arthritis, three (12%) Crohn's disease, and one (2%) ankylosing spondylitis patient. The median serum IFX trough level was significantly lower in patients with anti-IFX antibodies compared to those without antibodies [2.32 (IQR: 0.6-3.6) vs. 3.35 (IQR: 1.63-5.6); p = 0.019]. The serum IFX trough level was lower than the cut-off value in 6/13 (46%) patients with anti-IFX antibodies and in 25/158 (16%) patients without anti-IFX antibodies (p = 0.015). Among the four Behçet syndrome patients with anti-IFX antibodies, two experienced relapses and two had infusion reactions., Conclusions: Immunogenicity does not seem to be a frequent problem in Behçet syndrome patients treated with IFX, but may be associated with relapses and infusion reactions, when present., Competing Interests: GH has received grant/research support from Celgene and has served as a speaker for AbbVie, Celgene, Novartis, and UCB Pharma. 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 © 2020 Esatoglu, Akkoc-Mustafayev, Ozguler, Ozbakır, Nohut, Cevirgen, Hamuryudan, Hatemi, Celik, Yazici and Hatemi.)

Competing Interests: None

Objective: The aim of the study was to analyze the usefulness of CURB-65 and the pneumonia severity index (PSI) in predicting 30-day mortality in patients with COVID-19, and to identify other factors associated with higher mortality., Methods: A retrospective study was performed in a pandemic hospital in Istanbul, Turkey, which included 681 laboratory-confirmed patients with COVID-19. Data on characteristics, vital signs, and laboratory parameters were recorded from electronic medical records. Receiver operating characteristic analysis was used to quantify the discriminatory abilities of the prognostic scales. Univariate and multivariate logistic regression analyses were performed to identify other predictors of mortality., Results: Higher CRP levels were associated with an increased risk for mortality (OR: 1.015, 95% CI: 1.008-1.021; p < 0.001). The PSI performed significantly better than CURB-65 (AUC: 0.91, 95% CI: 0.88-0.93 vs AUC: 0.88, 95% CI: 0.85-0.90; p = 0.01), and the addition of CRP levels to PSI did not improve the performance of PSI in predicting mortality (AUC: 0.91, 95% CI: 0.88-0.93 vs AUC: 0.92, 95% CI: 0.89-0.94; p = 0.29)., Conclusion: In a large group of hospitalized patients with COVID-19, we found that PSI performed better than CURB-65 in predicting mortality. Adding CRP levels to PSI did not improve the 30-day mortality prediction., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: CYC remains an important treatment option for Behçet's syndrome (BS) patients with life-threatening manifestations. However, adverse events may occur with CYC and this has led to increased use of biologic agents in other vasculitides. We investigated short and long term adverse events associated with CYC use in BS patients., Methods: We conducted a retrospective chart review of all BS patients treated with CYC between 1972 and 2006. Patients were called in and a standard form was used for collecting demographic characteristics, indication for CYC, its cumulative dose and short term adverse events, defined as those causing discontinuation of CYC, hospitalization and/or death, long term adverse events, including infertility and malignancy, and outcome., Results: Of 5790 BS patients, 198 (3.4%) had used at least one dose of CYC. Main indications were vascular or neurological involvement. After a median follow-up of 17 years, 52 (26%) patients had died, 113 (57%) could be contacted, and 33 (17%) were lost to follow-up. Vascular involvement was the leading cause of death (n = 27). Seventeen (9%) patients experienced short term adverse events with haemorrhagic cystitis being the most common. After a median follow-up of 25 years (interquartile range: 15-26 years), 17 malignancies occurred in 15 (8%) patients. Infertility was experienced by 26 (30%) patients., Conclusion: Long term adverse events such as malignancy and infertility were major problems in our BS patients treated with CYC. These results underline the need for safer treatment modalities that are at least as effective as CYC., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The objective of the study is to assess the disease course and associated healthcare costs in a cohort of established rheumatoid arthritis (RA) patients in Turkey. The study cohort consisted of 75 RA patients from our outpatient clinic who took part in a previous multicenter study assessing RA-related healthcare costs 6 years ago. In March 2018, we attempted to re-evaluate these patients with the same questionnaire of the previous study enabling us to get information on medication use, comorbidities, and RA-related healthcare costs. We used RAPID-3 for assessing disease activity, HAQ-DI for functional status and EQ-5D for quality of life. Sixty-two (83%) patients were re-evaluated, seven (9.3%) had died and three (4%) were receiving palliative care following major cardiovascular events. Forty-seven (76%) patients had used at least one biologic agent during 79.1 ± 3.3 months after the previous study. At the last evaluation, 34 patients (55%) were on biologics, 22 (35%) were on csDMARDs and 6 (9.6%) were off RA treatment. The mean RAPID3 score (4.3 ± 1.6 SD) was similar to that of the previous study. HAQ-DI (0.69 ± 0.57 SD) and EQ-5D (0.68 ± 0.21 SD) scores showed significant improvement over time. Median direct costs (€2998) were higher than indirect costs (€304). Medication costs were high (€2958). Disease activity remained stable, while functional status and QoL had improved over time. Serious infections and cardiovascular disability are a concern. Medication costs are still the main determinant of RA-related healthcare costs.

The association between myelodysplastic syndrome (MDS) and Behçet syndrome (BS) is recognized for over 25 years. High frequency of trisomy 8 and intestinal ulcers are striking features of this association. There are no recommendations for how these patients should be treated. A systematic literature review was performed in PubMed using the keyword combination "(((((intestinal) OR gastrointestinal) OR ulcer) OR Behcet*)) AND ((myelodysplastic syndrome) OR MDS)" in March 2019. Our aim was to gain insight regarding clinical responses to individual treatment modalities. A recent case was also presented and included in the analysis. Data from 41 articles reporting on a total of 53 patients carried adequate information to assess treatment responses. Glucocorticoids provided benefit in 23 of 43 patients. Azacitidine, decitabine, thalidomide, and cyclosporine contributed to a clinical improvement in 4/6, 2/3, 3/4, and 5/8 patients respectively. Hematopoietic stem cell transplantation was successful in 9 of 13 patients. With the use of TNF inhibitors, azathioprine, and mesalamine derivatives, clinical improvement was observed in 3/11, 0/4, and 6/18 patients respectively. Patients with MDS and BS-like features who are resistant to glucocorticoids have so far benefited more from treatment approaches directed at MDS, rather than the immunosuppressive agents used for BS.

Objectives: Case reports and series suggest that Takayasu's arteritis (TAK) can co-exist with other inflammatory disorders. We conducted a formal study to look specifically at the frequency of such inflammatory disorders in a large cohort of TAK followed by a single tertiary centre., Methods: There were 238 patients registered with a diagnosis of TAK. Of these, 19 died, 18 were lost to follow-up and 3 did not wish to respond to our questionnaire. The remaining 198 (175 F/23 M) patients were called back at the outpatient clinic. A standardised form sought whether the patient was also diagnosed with inflammatory bowel disease (IBD), ankylosing spondylitis (AS), Behçet's syndrome (BS), autoimmune or any other inflammatory disorder. The presence of skin-mucosa lesions, inflammatory eye disease and inflammatory back pain were also specifically sought for., Results: We identified 37 (19%) patients with inflammatory bowel disease (n=12, 6%), ankylosing spondylitis (n=15, 8%) or Behçet's syndrome (n=10, 5%). Thirteen (6.5%) patients had systemic or localised autoimmune disease and 9 (4.5%) miscellaneous inflammatory diseases. Among the 139 patients without any concomitant disease, inflammatory back pain (n=49, 35%) was the most common feature, followed by recurrent oral ulcer (n=20, 14%) erythema nodosum (n=17, 12%), arthritis (n=12, 9%) papulopustular lesions (n=8, 6%) and uveitis/scleritis (n=6, 4%). Only 64 patients (32%) did not have any concomitant disease/condition or specific clinical feature., Conclusions: TAK does co-occur with IBD, AS and less frequently with BS in about 1/5 of the patients, at least in a hospital setting. There is no clear temporal pattern. The high prevalence of inflammatory back pain in the dorsal spine in TAK needs further scrutiny.

Objectives: We investigated cardiovascular surgical interventions in a group of patients with Takayasu's arteritis (TAK) diagnosed and followed by a single centre., Methods: . Twenty patients with TAK (5 males, 15 females, mean current age: 38.1±10.7) who were operated for a broad spectrum of cardiovascular diseases ranging from coronary heart disease to coeliac stenosis or aneurysm between July 2008 and April 2016 were studied. One patient underwent operation related to aneurysm of ascending aorta and aortic insufficiency, 2 patients had operations for both coronary arteries originating from aortic arch, 6 patients for only arteries originating from aortic arch, 1 patient for both carotid and infra-inguinal artery, 5 patients for aorta-iliac or femoral revascularisation, 5 patients for renal artery and/or coeliac or superior mesenteric artery revascularisations. Three of these interventions were endarterectomy and patch plasty., Results: The mean time between diagnosis and surgical intervention was 6.1±3.1 years (range: 3 months-12 years). A total of 4/32 (12.5%) grafts were occluded during the follow up period of mean 39.2±24.6 months. Secondary interventions like cross-femoral, or graft to superficial femoral artery bypasses were needed in 2 patients who underwent aorta-bifemoral bypasses to keep patency. There was no operative mortality. We did not observe any anastomotic aneurysm. One patient died due to graft infection 3 months after the operation. Stroke occurred in 2 patients who underwent re-vascularisations of the arteries originating from aortic arch., Conclusions: In our series, we have a relatively good midterm patency rates in patients with TAK and did not observe any anastomotic pseudoaneurysm. Stroke developed in 2 patients and mortality occurred in one patient due to the graft infection 3 months after the operation. In patients with limited carotid or aorta-iliac stenosis, chance for endarterectomy should be evaluated. Well-controlled disease activity with intensive medical treatment and multi-disciplinary approach could be associated with a favourable long-term outcome.

Objectives: Systemic therapy aimed at suppressing the diffuse inflammation in the vessel wall is the major treatment modality for venous thrombosis in Behçet's syndrome (BS). Endovascular and/or surgical interventions are also used. We here report five patients who were referred to our clinic after having such interventions and also present a literature review to assess the outcome of invasive procedures for venous thrombosis in BS., Methods: Our patients were presented and a literature search for endovascular and/or surgical interventions in Pub-Med was performed. Recanalisation, reocclusion or other complications were assessed as outcomes., Results: Five BS patients with lower extremity thrombosis were referred to our clinic with post thrombotic syndrome due to incomplete recanalisation or infectious complication after endovascular interventions. Twenty-one articles reporting on 36 patients were found suitable for review. There were totally 21 lower extremity venous intervention cases, 14 of which had failure such as complication, reocclusion or incomplete recanalisation. Reocclusions occurred in 10 patients and reinterventions to 8 of them could restore flow only in 4 cases. Ileal infarct and vena cava wall-duodenal perforation were major complications. Invasive procedures of 8 abdominal thrombosis cases resulted with death due to ileus in one patient, and reocclusion in another. Seven of the 12 upper extremity/superior vena cava thrombosis cases resulted with reocclusions., Conclusions: Endovascular and surgical interventions seemed to be unsuccessful because of recurrent infectious and vascular complications in 22 (53.6%) of 41 patients with venous thrombosis. The indication of these procedures is controversial. Their economic burden on the healthcare system must be considered.

Objectives: Superior vena cava syndrome (SVCS) is a medical emergency which can also be seen in Behçet's syndrome (BS). Having noted that BS patients with SVCS frequently complained of sleep disturbances, snoring and sleep apnea, suggesting obstructive sleep apnea (OSA), we formally surveyed the risk for OSA among BS patients., Methods: We studied 28 patients, all male, with SVCS (Group 1), 129 with vascular involvement without a SVCS (Group 2) and 151 with no vascular involvement (Group 3). In addition, 100 apparently healthy individuals (Group 4) were studied. The Berlin questionnaire (BQ), a validated screening tool with a high sensitivity and modest specificity that identifies individuals with high-risk for OSA, was administered to all study participants., Results: The study groups were similar with regard to age (Group 1, mean age: 44.3±9.7; Group 2, mean age: 41.5±8.7, Group 3, mean age: 40.4±9.4 and Group 4, mean age: 42.1±9.4) mean body mass index and the frequency of hypertension and other comorbidities. The frequency of those patients at high-risk for OSA according to the BQ was 57%, 17%, 17% and 11% in Groups 1, 2, 3 and 4, respectively (p<0.05). Age-adjusted ORs of OSA compared to healthy controls (Group 4) was 11.00 (95%CI: 4.01-30.07) for Group 1, 1.78 (95%CI: 0.81-3.94) for Group 2, 1.92 (95%CI: 0.90-4.14) for Group 3., Conclusions: BS patients with SVCS are at high risk for OSA. This is probably due to the external pressure of the significant presence of venous collaterals that surround the upper airways. Our results should be further confirmed by polysomnography, and future research should be carried out to clarify the causes of this association.

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.

Behçet's syndrome (BS) is a complex disease that shows important heterogeneity in clinical findings and physiopathology. Its treatment can be problematic as BS manifestations in different organs may respond differently to the same drug. The cornerstone of therapy for inducing remission is corticosteroids whereas immunomodulatory and immunosuppressive agents such as colchicine, azathioprine, cyclosporine-A, interferon-alpha, and cyclophosphamide are used as steroid-sparing agents and to prevent further relapses. However, a considerable number of patients continue to have mucocutaneous lesions despite therapy, and some patients require more aggressive treatment for refractory major organ involvement. Tumor necrosis factor alpha inhibitors, especially infliximab and adalimumab, are increasingly used for various refractory BS manifestations despite the lack of controlled studies. In this review, we aim to focus on both the traditional and new treatment modalities for BS, with more emphasis on recent data on newer agents.

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.)

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.

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.

Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.