Alessandra Bettiol’s research while affiliated with University of Florence and other places

Eosinophilic granulomatosis with polyangiitis (EGPA) is a chronic inflammatory disease belonging to the spectrum of small-vessel vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs), also characterized by eosinophilic infiltration of target organs. Peripheral neuropathy (PN) affects about 2/3 of the patients as a presenting symptom and typically represents a vasculitic involvement. A few studies have addressed the role of intravenous immunoglobulin (IVIg) for the treatment of PN in EGPA. This monocentric retrospective study aims at assessing the effectiveness and safety of IVIg in patients with PN as the main acute manifestation at EGPA onset. The treatment with IVIg appears to be effective in inducing sustained remission, reducing the risk of relapses and improving the long-term disability due to its effects on PN.

Fibrinogen, a blood plasma protein with a key role in hemostasis and thrombosis, is highly susceptible to post-trans-lational modifications (PTMs), that significantly influence clot formation, structure, and stability. These PTMs, which include acetylation, alter fibrinogen biochemical properties and affect its functional behavior in coagulation and fibrinolysis. Oxidation and nitration are notably associated with oxidative stress, impacting fibrin fiber formation and promoting the development of more compact and resistant fibrin networks. Glycosylation and glycation contribute to altered fibrinogen structural properties, often resulting in changes in fibrin clot density and susceptibility to lysis, particularly in metabolic disorders like diabetes. Acetylation and phosphorylation, influenced by medications such as aspirin, modulate clot architecture by affecting fiber thickness and clot permeability. Citrullination and homocysteinylation, although less studied, are linked to autoimmune conditions and cardiovascular diseases, respectively, affecting fibrin formation and stability. Understanding these modifications provides insights into the pathophysiology of thrombotic disorders and highlights potential therapeutic targets. This review comprehensively examines the current literature on fibrinogen PTMs, their specific sites, biochemical pathways, and their consequences on fibrin clot architecture, clot formation and clot lysis.

Reactive oxygen species (ROS) contribute to endothelial dysfunction, platelet activation, and coagulation abnormalities, promoting thrombus formation. Given the growing interest in non-pharmacological approaches to modulate oxidative stress, we examine the potential of various dietary interventions and antioxidant supplementation in reducing oxidative damage and preventing thrombotic events. Key dietary patterns, such as the Mediterranean, Dietary Approaches to Stop Hypertension (DASH), and ketogenic diets, as well as antioxidant-rich supplements like curcumin, selenium, and polyphenols, demonstrate promising effects in improving oxidative stress markers, lipid profiles, and inflammatory responses. This review highlights recent advances in the field, drawing from in vitro, ex vivo, and clinical studies, and underscores the importance of integrating dietary strategies into preventive and therapeutic approaches for managing thrombosis and cardiovascular health. Further research is needed to better understand long-term effects and personalize these interventions for optimizing patient outcomes.

Background Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterised by asthma, ear-nose-throat (ENT) involvement, and systemic vasculitic manifestations. [1] Interleukin (IL)-5 inhibitors are currently used for EGPA treatment, controlling both respiratory and systemic manifestations. [2-5] Objectives This study aimed to compare the efficacy and safety of the anti-IL5 drug mepolizumab to the IL-5 receptor antagonist benralizumab in a European cohort of patients with EGPA. Methods A retrospective observational cohort study was conducted on EGPA patients treated with mepolizumab or benralizumab at the dosage approved for eosinophilic asthma at 47 centers belonging to the European EGPA Study Group. Patients in the benralizumab group were matched 1:1 to those in the mepolizumab one, by sex, age (± 5 years), Birmingham Vasculitis Activity Score (BVAS) (± 2) and oral corticosteroids (OCS) dosage (± 2.5mg/day) at time of treatment beginning (T0), and data were then compared after 3, 6, and 12 months. Complete response (CR) was defined as no disease activity (BVAS= 0) and OCS dose ≤4mg/day; OCS tapering was evaluated considering the ongoing dosage at each timepoint. Pulmonary function (variation in the forced expiratory volume in 1 second [FEV1] expressed as ΔFEV1) and safety outcomes were compared over a 12-month follow-up. Results 88 EGPA patients treated with mepolizumab and 88 with benralizumab were matched according to a pre-defined set of baseline variables. Fifty patients in each group (57.0%) were female, with a median age at T0 of 54 years (IQR 23-45). Baseline characteristics at T0 is reported in Figure 1 . CR remarkably increased during follow-up in both groups. At T3, CR was reported in 12/88 patients (13.6%, 95% CI 7.2-22.6%) in mepolizumab group and 9/88 patients (10.2%, 4.8-18.5%) in benralizumab cohort (p=0.485). At T6, the CR rates increased to 18/83 patients (21.7%, 13.4-32.1%) in the mepolizumab cohort and 21/66 (31.8%, 20.1-44.4%) respectively (p=0.128), reaching 22/68 (32.4%, 21.5-44.8%) and 25/52 (48.1%, 34.0-62.4%) at T12, respectively (p=0.005). Moreover, a reduction of BVAS was observed in both cohorts with no statistical differences at each timepoint. (Figure 2 ) A OCS-sparing effect was observed in both groups, the daily OCS dose decreasing from 10 mg/day (IQR 5– 12.5) to 5 mg/day (3-7.5) at T3, 5 mg/day (1.3-5) at T6, and 4 mg/day (0-4.5) at T12 in the mepolizumab cohort, and from 10 mg/day (7-13) to 5 mg/day (5-8) at T3, 5 mg/day (2-5) at T6, and 2.5 mg/day (0-5) at T12 in the benralizumab cohort. No differences were observed when comparing the daily OCS dosage between the two groups at T3 (p=0.467), T6 (p=0.823) and T12 (p=0.115). (Figure 2 ) Under treatment with mepolizumab, 5 patients relapsed after achieving CR: 2 relapses occurred at T6 and 3 at T12; under treatment with benralizumab, 4 patients relapsed after achieving CR at T12. Compared to baseline values, an improvement in FEV1 was observed in both cohort with no statistically significant differences between the two groups [from T0 to T3: +6.6% (IQR2-17.5) for mepolizumab vs +13.7% (4.4-22.1) for benralizumab (p=0.039); from T0 to T6: +12.0% (2.1-16.5) vs +14.7% (7.73-29.3) (p=0.669); from T0 to T12: +10.6% (4.7-25.9) vs +13.2% (0.1-43.9) (p=0.267)]. Concerning the safety profile, 11 patients (12.5%) reported adverse events during treatment with mepolizumab and 15 (17.0%) with benralizumab. Most events were mild, with only one on mepolizumab and 2 on benralizumab requiring hospitalization. Finally, 9/88 (10%) patients discontinued mepolizumab and 16/88 (18%) discontinued benralizumab (p= 0.130). Conclusion These results suggest that mepolizumab and benralizumab at the dosage approved for eosinophilic asthma showed comparable effectiveness in controlling systemic and respiratory involvement, and both treatments were associated with a good safety profile. REFERENCES [1] Fagni Front Med 2021.[2] Bettiol Arthritis Rheumatol (Hoboken, NJ) 2022. [3] Bettiol Ann Rheum Dis 2022. [4] Cottu Ann Rheum Dis 2023. [5] Bettiol Lancet Rheumatol 2023. • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Acknowledgements EGPA Study Group. Disclosure of Interests Irene Mattioli: None declared, Alessandra Bettiol: None declared, Vincent Cottin GSK and AstraZeneca, GSK and AstraZeneca, GSK and AstraZeneca, Allyson Egan: None declared, Franco Franceschini: None declared, Matthieu Groh GSK and AstraZeneca, David R. W. Jayne Amgen, AZ, Aurinia, GSK, Novartis, Roche, Takeda, CSL-Vifor, Amgen, AZ, Aurinia, GSK, Novartis, Roche, Takeda, CSL-Vifor, Giuseppe Lopalco: None declared, Thomas Neumann: None declared, Roberto Padoan GSK, GSK, Jan Schroeder: None declared, Augusto Vaglio GSK and AstraZeneca, GSK and AstraZeneca, Giacomo Emmi GSK and AstraZeneca, GSK and AstraZeneca.

Background Research in the field of ANCA-associated vasculitis (AAV) is hampered by diseases rarity along with the subsequent small sample sizes of observational cohorts. The latter are also complicated by the fragmented nature of data pools, lacking in standardization and in deriving data interoperability. Objectives FAIRVASC is a Europe-based research project [1], which aimed to develop a web-based infrastructure linking 7 existing AAV registries into a single dataset, to allow for high-quality research regarding both natural disease history and clinical outcomes. The analysis performed in this study further highlights the promising capabilities of the FAIRVASC infrastructure to assess clinical outcome of AAV across the federated registries. Methods The 7 national AAV registries currently present within the FAIRVASC project were harmonized through a semantic web approach, including the creation of a dedicated AAV ontology enabling semantic interoperability. For this study, aggregated mortality rate data (number of deaths/100 person years, with related 95% Confidence Intervals) stratified per diagnosis were retrieved through the FAIRVASC web-based interface, a tool allowing for federated querying over the linked registries. We defined mortality rate across different timepoints: in the first- and second-year post diagnosis, in years 3-5 and after 5 years. Results Mortality rates were queried over the FAIRVASC registries, namely RKD (Republic of Ireland, 677 patients), GFEV (France, 2814 pts), ANCA (Czech Republic, 377 pts), PolVas (Poland, 944 pts), Skane (Sweden, 374 pts), Italivas (Italy, 301 pts), GeVas (Germany, 169 pts). Mortality rates, stratified both by diagnosis and registry, are reported in Table 1 The lowest mortality was reported for eosinophilic granulomatosis with polyangiitis (EGPA), with rates ranging from 0 to 2.5 cases/100 person-years depending on the post-diagnosis interval. Conversely, the highest mortality was found for microscopic polyangiitis (MPA), with mortality rates ranging from 0.09 to 22.3 across registries in the first year after diagnosis, and from 3.9 to 7.4 after >5 years from diagnosis. In patients with granulomatosis with polyangiitis (GPA), mortality rates ranged from 0 to 8.2 in the first year after diagnosis and from 0 to 4.5 after >5 years from diagnosis. Conclusion The FAIRVASC infrastructure represents a reliable tool to interrogate multiple AAV registries in order to assess long-term AAV clinical outcomes in a large number of patients, maintaining a privacy-compliant approach. REFERENCES [1] McGlinn K, Rutherford MA, Gisslander K, Hederman L, Little MA, O’Sullivan D. FAIRVASC: A semantic web approach to rare disease registry integration. Comput Biol Med. 2022 Jun;145:105313. doi: 10.1016/j.compbiomed.2022.105313. Epub 2022 Mar. Table 1 Mortality rate (cases/100 person years with 95% CI) over FAIRVASC registries • Download figure • Open in new tab • Download powerpoint Acknowledgements NIL Disclosure of Interests None declared

Background Treatment with glucocorticoids (GC), often combined with immunosuppressants, effectively induces remission in the majority of cases (75-95%) of chronic periaortitis (CP) [1]. However, a significant proportion of patients (up to 75%) experience relapses. The predictors of remission and relapse in patients with CP have never been explored. Objectives The aim of this study was to identify predictors of remission and relapse in a large cohort of patients with CP. Methods We retrospectively reviewed the charts of consecutive adult CP patients referred to three Italian referral centres between January 2006 and February 2021. To be included, patients were required to have baseline and post-treatment CT, 18F-FDG PET, or MRI scans, and to have undergone a 9-to-12-month treatment protocol with glucocorticoids, with or without other immunosuppressants.Statistical Analysis: Logistic univariate and multivariate regression models were employed to assess remission probability based on baseline demographic and clinical parameters. Risk of relapse, at baseline, month 4, and end of treatment (EOT), was evaluated with Cox univariate and multivariate regression models. Measurement of vascular uptake at 18F-FDG PET was graded using a 4-point (0 to 3) semiquantitative scale. Metabolic responses were classified as complete, partial, stable or progressive disease according to PERCIST criteria [2]. Remission was defined as the disappearance of disease-related symptoms, normalization of ESR and CRP and a decrease/stabilization of the mass on imaging. Relapse was defined as recurrence of disease-related symptoms or enlargement of the mass on imaging. Results One hundred and fifteen patients, with a mean follow-up of 33 (17-57) months, were included in this study. Baseline characteristics and treatments are reported in Table 1. Of the 115 patients, 101 (87%) achieved remission, with a median time to remission of 4 (3-5) months. Among the 101 patients who achieved remission, 42 (42%) experienced a relapse, with a median time to relapse of 14 (8-26) months. Smoking habit (OR 0.34, 95% CI 0.11-0.99, p=0.049) and an atypical CP (i.e., pelvic, pre-sacral) localization (OR 0.11, 95% CI 0.02-0.52, p=0.005) were identified as negative independent predictors of remission. Conversely, PET-CT uptake at baseline (grade 0 vs grade 1-3) emerged as a positive predictor of remission (OR 11.51, 95% CI 1.35-98.20, p=0.025). In terms of predictors of relapse (Figure 1), thoracic vessel involvement and a positive 18FDG-PET at EOT were identified as positive independent predictors of relapse (HR 2.61, 95% CI 1.19-5.68, p=0.016 and HR 3.47, 95% CI 1.54-7.82, p=0.003 respectively). Conclusion Disease activity on PET-CT at baseline emerges as an independent predictor of remission (when positive at baseline) and of relapse (when positive at EOT). Other factors are also to be considered as prognostic factors for remission (smoking and atypical CP localisation) and relapse (thoracic vessel involvement). These findings may guide treatment choices in patients with CP. REFERENCES [1] Palmisano A et al, Curr Rheumatol Rep, 2018.[2] Wahl R et al, J Nucl Med, 2009. Table 1 • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Figure 1. Acknowledgements NIL Disclosure of Interests Milena Bond Abbvie, Galapagos, Abbvie, Alessandra Bettiol: None declared, Eugenia Accorsi Buttini: None declared, Giacomo Emmi: None declared, Augusto Vaglio: None declared.

Stroke is one of the most common causes of mortality and disability worldwide. Antithrombotic therapy represents the mainstay in primary and secondary prevention, both in cardioembolic and non-cardioembolic stroke. Particularly, direct oral anticoagulants play a crucial role in atrial fibrillation, the most common cause of cardioembolic stroke, whereas single or dual antiplatelet therapy is preferred in non-cardioembolic stroke. However, the limitations related to the residual risk of cardioembolic or cerebrovascular events, and the risk of major bleeding, still represent unmet medical needs. To overcome them, new drugs inhibiting Factor XI (FXI) and Factor XII have been proposed, with a selective inhibition of contact pathway of coagulation, delineating a new anticoagulant approach. This review provides a summary of the currently available evidence and future perspectives on FXI inhibitors, that can represent an additional therapeutic option in the primary and secondary prevention of cardioembolic and non-cardioembolic ischemic stroke, also in challenging therapeutic contexts. Graphical Abstract

Objectives To estimate the incidence and prevalence of SLE in Italy, and to describe the demographic and clinical characteristics of patients with newly diagnosed SLE. Methods A retrospective cohort study was conducted using The Health Improvement Network general practice database in Italy, encompassing data from 634 753 people. SLE cases were identified over the period 2017–2022, employing three alternative definitions to provide a more detailed understanding of SLE characteristics. Incidence rates were expressed as cases per 100 000 person-years and prevalence as cases per 100 000 people. Demographic and clinical characteristics of incident SLE cases were also studied. Results From 2017 to 2022, a total of 191 incident and 1385 prevalent cases were identified under our first definition. In 2022, the incidence rate was 6.51 cases (95% CI 6.29 to 6.74) per 100 000 person-years, and the prevalence 60.57 (95% CI 59.89 to 61.25) per 100 000 people, being the prevalence five times higher in women compared with men. Both estimates have trended upwards since 2017. A geographical variation across the country was also seen. The demographic and clinical characteristics of incident SLE cases were described, while the potential associations of SLE incidence with some pre-existing conditions were observed, such as chronic kidney disease, chronic hepatic disease, rheumatoid arthritis and Sjogren’s syndrome. Conclusions The results of this nationwide study, the first conducted in Italy, showed that the incidence of SLE has increased in Italy in recent years. Age, sex, and area of residence strongly correlate with the epidemiology of this condition.