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Introduction: Evidence from randomised controlled trials on anti-tumour necrosis factor (TNF) agents in patients with Behçet's syndrome (BS) is low., Method: We conducted a phase 3, multicentre, prospective, randomised, active-controlled, parallel-group study to evaluate the efficacy and safety of either infliximab (IFX) or adalimumab (ADA) in patients with BS. Adults patients with BS presenting with active mucocutaneous manifestations, occurring while on therapy with either azathioprine or cyclosporine for at least 3 months prior to study entry, were eligible. Participants were randomly assigned (1:1) to receive IFX or ADA for 6 months. The primary study outcome was the time to response of manifestations over 6-month anti-TNF alpha agents' treatment., Results: 42 patients underwent screening visits, of whom 40 were randomly assigned to the IFX group (n=22) or to the ADA group (n=18). All patients at the time of randomisation had active mucocutaneous manifestations and a smaller proportion had concomitant vital organ involvement (ie, six and three patients with ocular and neurological involvement, respectively). A total of 14 (64%) responders in the IFX group and 17 (94%) in the ADA group were observed. Retention on treatment was 95% and 94% in the IFX and in the ADA group, respectively. Quality of life resulted to be significantly improved in both groups from baseline, as well as Behçet's Disease Current Activity Form assessment. We registered two adverse events (one serious) in the ADA group and three non-serious adverse events in the IFX group., Discussion: The overall results of this study confirm the effectiveness of both IFX and ADA in achieving remission in patients with BS affected by mucocutaneous involvement., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ on behalf of EULAR.)

Behçet's syndrome (BS) is a rare multisystem vasculitis involving blood vessels of any size. BS aetiology is still unclear to date, and the heterogeneity of clinical expression among ethnics and genders make early diagnosis challenging. However, so far, considerable efforts have been made toward the understanding of BS, leading researchers to agree that the coexistence of some environmental triggers and a genetical susceptibility both underlie BS aetiopathogenesis. In particular, viral agents, oral microbial flora, and mucosal microbiota have been widely explored in this regard, but still no specific microorganism has been definitely linked to the disease aetiology. Likewise, the concept that some environmental factors may play a role in BS clinical presentation has emerged based on the growing evidence that disease severity is usually higher in male patients, and that diet and fatigue may be involved in disease recurrence, especially in mucocutaneous manifestations. Moreover, smoke cessation is acknowledged as a risk factor for oral ulcerations, although the underlying mechanism is still not clear. All those environmental factors play their effects through epigenetic mechanisms. The aim of this review is to discuss the evidence on the role of environmental factors in BS aetiopathogenesis and clinical course.

Behçet's syndrome (BS) is a rare chronic multi-systemic inflammatory disorder that usually involves adults between third and fourth decades of life, while pediatric and juvenile onset are relatively rare. BS young patients (YP) often develop a full-blown disease late after onset, requiring careful diagnostic workup and regular follow-up while they grow up. In this regard, the purpose of transitional programs is to ensure continuous high-quality care to YP with chronic conditions, providing them with the skills necessary to become independent and empowered adults able to chronically self-manage their disease. EULAR/PReS released the first set of standards and recommendations for transitional care (TC) of YP with juvenile-onset rheumatic diseases, but the appropriate timing for transition, the tools to evaluate patients' readiness, and indicators of transition plans effectiveness still need to be identified. Although little is known regarding TC in BS, it is easy to assume that BS YP will benefit from developmentally and disease-specifically appropriate transition plans, which may promote continuity of care, improve perceived quality of life and prevent poor disease outcomes. This perspective article discusses the key concepts and the goals of TC, addressing the potential challenges and opportunities of TC for YP with BS in clinical practice., Competing Interests: The 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 © 2024 Di Cianni, Mastrolia, Biancalana, Marinello, Emmi, Mosca, Simonini and Talarico.)

Objectives: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic pauci-immune necrotising vasculitides involving small vessels, characterised by the presence of specific ANCA autoantibodies directed to leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) and subdivided into three clinical entities: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The aetiology of AAV is unknown and many genetic, epigenetic and environmental factors have been reported to be involved in pathogenesis. Smoking is widely recognised as a risk factor for the development of many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. This systematic review will analyse known data about the role of smoking in the development, clinical presentation and outcome of AAV., Methods: Articles that examined interactions between tobacco smoking and AAV (GPA, MPA, EGPA) were included. All articles selected were in English. No limitation on publication date was established. Case reports were excluded. The systematic search was performed using PubMed/Medline and Cochrane Library databases., Results: The search provided a total of 131 articles. Three studies were added, obtained from the review of the reference lists of articles. 70 were removed because they were duplicated or written in languages other than English. The title and abstract of 64 articles were screened. Of these, 30 were excluded as the title and/or abstract did not meet the inclusion criteria. Thus, 34 remained for full-text review, of which 8 were excluded. 26 articles were therefore included in this review. The role of smoking in AAV development is unclear. AAV patients current smoking appear appear to be younger and more frequently males, with a lower prevalence of EGPA and MPA than GPA. Ever smokers show higher relapse rate. Smoking seems to be associated with a higher risk of cardiovascular events during follow-up. Smokers incur an increased risk of infections. Finally, many data support smoking as a risk factor for end stage renal disease and mortality in AAV patients., Conclusions: Current data support the hypothesis that smoking influences prevalence, clinical phenotype and prognosis of ANCA-associated vasculitis. However, further studies are required to fully determine its role.

Systemic vasculitides comprise a collection of rare and heterogeneous disorders capable of impacting any organ and system, posing a considerable burden of mortality and comorbidity. As with previous annual reviews of this series, this review will offer a critical overview of the latest literature on pathogenesis, biomarkers, and treatment options in both small- and large-vessel vasculitis.

Systemic vasculitides are heterogeneous disabling diseases characterised by chronic inflammation of the blood vessels potentially leading to tissue destruction and organ failure. The recent COVID-19 pandemic has had a significant impact on the epidemiology and management of patients with systemic vasculitis. In parallel, new insights have been provided on systemic vasculitis pathogenetic mechanisms, possible new therapeutic targets, and newer glucocorticoid-sparing treatments with better safety profiles. As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis focusing on precision medicine in vasculitis.

Objectives: The assessment of quality of life (QoL) in Behçet's disease (BD) patients has been a surrogate of disease outcomes, but a wider impact on the patient's lifestyle has not been considered. This systematic review aims to provide an overview of the existing tools specifically adopted to explore the QoL in BD patients., Methods: A systematic literature review was conducted using 2 electronic databases, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A combination of BD and QoL-related search terms were used. All articles were screened by 3 independent reviewers for title, abstract and full text level. Studies investigating QoL in BD patients were included., Results: 64 papers of 497 records were retained. Data about 7,449 patients with a BD diagnosis and QoL evaluation were collected. 47 different tools to evaluate QoL were detected. The mean number of tools adopted in each study was 2.14±1.34. General QoL and psychological and social impact were investigated in 68.75% and 54.69% respectively. The correlation with disease activity was investigated in 71.86%., Conclusions: The assessment of QoL in BD patients may provide a fundamental measurement for health to evaluate the outcome of interventions for BD patients. The adoption of a single validated QoL tool, developed including the BD patient's perspective, may provide an accurate and effective assessment, ensure the comparison within different cohorts, and set standardised values to define QoL level in BD patients.

Systemic vasculitis are rare heterogeneous disorders potentially involving any organ and system with a relevant burden of mortality and comorbidity.As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis.

Behçet's syndrome (BS) represents a challenging condition, characterized by a variable spectrum of disease profile and associated with a significant limitation of the daily activities as well as a potential negative impact on relationships and psychological status. Considering also the complexity of the therapeutic management of BS, that often includes biological off-label treatments, the participation in the therapeutic decision-making process of the BS patients is essential to ensure the integration of the care process into the life of the patient. For this reason, the empowerment of BS patients represents a crucial need and the present work is aimed at fully exploring all the potential variables implicated in the BS patient empowerment, also highlighting major points to consider and concrete actions to be planned in the immediate future in order to implement a pragmatic facilitation of the patients' empowerment., Competing Interests: The 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 Marinello, Di Cianni, Del Bianco, Mattioli, Sota, Cantarini, Emmi, Leccese, Lopalco, Mosca, Padula, Piga, Salvarani, Taruscio and Talarico.)

Objectives: In patients with systemic autoimmune rheumatic disorders (SARDs), vaccination with SARS-CoV-2 mRNA vaccines has been proposed. The aim of this study is to evaluate the immune response elicited by vaccination with mRNA vaccine, testing IgM, IgA and IgG antibodies to SARS-CoV-2 receptor-binding domain (RBD) and measuring neutralising antibodies., Methods: IgG, IgM and IgA anti-RBD antibodies were measured in 101 patients with SARDs. Antibodies inhibiting the interaction between RBD and ACE2 were evaluated. Antibody avidity was tested in a chaotropic ELISA using urea. Twenty-one healthcare workers vaccinated with mRNA vaccine served as control group., Results: Anti-RBD IgG and IgA were produced after the first dose (69% and 64% of the patients) and after the boost (93% and 83%). Antibodies inhibiting the interaction of RBD with ACE2 were detectable in 40% of the patients after the first dose and 87% after boost, compared with 100% in healthy controls (p<0.01). Abatacept and mycophenolate had an impact on the titre of IgG anti-RBD antibodies (p<0.05 and p<0.005, respectively) and on the amount of neutralising antibodies. No effect of other therapies was observed. Vaccinated patients produce high avidity antibodies, as healthy controls., Conclusions: These data show that double-dose vaccination induced in patients with SARDs anti-RBD IgG and IgA antibodies in amounts not significantly different from controls, and, most interestingly, characterised by high avidity and endowed with neutralising activity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Large- and small-vessel vasculitis are complex potentially life-threatening systemic autoimmune diseases that have recently been subjected to considerable immunologic and clinical research. Following the other reviews of this series, here we aim to summarise some of the most significant studies that have been recently published on the pathogenesis, clinical features and novel treatments of systemic vasculitis.

The pathways that regulate energy homeostasis, the mechanisms of damage repair, and the signaling response to internal environmental changes or external signals have been shown to be critical in modulating lifespan of model organisms and humans. In order to investigate whether genetic variation of genes involved in these pathways contribute to longevity, a two-stage case-control study in two independent sets of long-lived individuals from Calabria (Italy) was performed. In stage 1, 317 SNPs in 104 genes were analyzed in 78 cases (median age 98 years) and 71 controls (median age 67 years). In stage 2, 31 candidate SNPs identified in stage 1 (π markers = 0.1) were analyzed in an independent sample composed by 288 cases (median age 92 years) and 554 controls (median age 67 years). Two SNPs, rs282070 located in intron 1 of the MAP3K7 gene, and rs2111699 located in intron 1 of the GSTZ1 gene, were significantly associated (after adjustment for multiple testing) with longevity in stage 2 (p = 1.1 × 10(-3) and p = 1.4 × 10(-3), respectively). Interestingly, both genes are implicated in the cellular response to internal and external environmental changes, playing a crucial role in the inflammation processes that accompany aging. Our data confirm that long-lived subjects are endowed with genetic variants that allow them to optimize these cellular responses and to better deal with environmental and internal stresses.

Human SIRT3 gene contains an intronic VNTR enhancer. A T > C transition occurring in the second repeat of each VNTR allele implies the presence/absence of a putative GATA binding motif. A partially overlapping AP-1 site, not affected by the transition, was also identified. Aims of the present study were: 1) to verify if GATA and AP-1 sites could bind GATA2 and c-Jun/c-Fos factors, respectively; 2) to investigate whether such sites modulate the enhancer activity of the SIRT3-VNTR alleles. DAPA assay proved that GATA2 and c-Jun/c-Fos factors are able to bind the corresponding sites. Moreover, co-transfection experiments showed that the over-expression of GATA2 and c-Jun/c-Fos factors boosts the VNTR enhancer activity in an allelic-specific way. Furthermore, we established that GATA2 and c-Jun/c-Fos act additively in modulating the SIRT3-VNTR enhancer function. Therefore, GATA2 and AP-1 are functional sites and the T S> C transition of the second VNTR repeat affects their activity.

Background: Recent technological advances in DNA sequencing and genotyping have led to the accumulation of a remarkable quantity of data on genetic polymorphisms. However, the development of new statistical and computational tools for effective processing of these data has not been equally as fast. In particular, Machine Learning literature is limited to relatively few papers which are focused on the development and application of data mining methods for the analysis of genetic variability. On the other hand, these papers apply to genetic data procedures which had been developed for a different kind of analysis and do not take into account the peculiarities of population genetics. The aim of our study was to define a new similarity measure, specifically conceived for measuring the similarity between the genetic profiles of two groups of subjects (i.e., cases and controls) taking into account that genetic profiles are usually distributed in a population group according to the Hardy Weinberg equilibrium., Results: We set up a new kernel function consisting of a similarity measure between groups of subjects genotyped for numerous genetic loci. This measure weighs different genetic profiles according to the estimates of gene frequencies at Hardy-Weinberg equilibrium in the population. We named this function the "Hardy-Weinberg kernel". The effectiveness of the Hardy-Weinberg kernel was compared to the performance of the well established linear kernel. We found that the Hardy-Weinberg kernel significantly outperformed the linear kernel in a number of experiments where we used either simulated data or real data., Conclusion: The "Hardy-Weinberg kernel" reported here represents one of the first attempts at incorporating genetic knowledge into the definition of a kernel function designed for the analysis of genetic data. We show that the best performance of the "Hardy-Weinberg kernel" is observed when rare genotypes have different frequencies in cases and controls. The ability to capture the effect of rare genotypes on phenotypic traits might be a very important and useful feature, as most of the current statistical tools loose most of their statistical power when rare genotypes are involved in the susceptibility to the trait under study.