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Objectives: The cerebral vessels may be affected in primary systemic vasculitis (PSV), but little is known about cerebrovascular events (CVEs) in this population. This study aimed to determine the frequency of CVEs at the time of diagnosis of PSV, to identify factors associated with CVEs in PSV, and to explore features and outcomes of stroke in patients with PSV., Methods: Data from adults newly diagnosed with PSV within the Diagnostic and Classification Criteria in VASculitis (DCVAS) study were analysed. Demographics, risk factors for vascular disease, and clinical features were compared between patients with PSV with and without CVE. Stroke subtypes and cumulative incidence of recurrent CVE during a prospective 6-month follow-up were also assessed., Results: The analysis included 4828 PSV patients, and a CVE was reported in 169 (3.50%, 95% CI 3.00-4.06): 102 (2.13% 95% CI 1.73-2.56) with stroke and 81 (1.68% 95% CI 1.33-2.08) with transient ischemic attack (TIA). The frequency of CVE was highest in Behçet's disease (9.5%, 95% CI 5.79-14.37), polyarteritis nodosa (6.2%, 95% CI 3.25-10.61), and Takayasu's arteritis (6.0%, 95% CI 4.30-8.19), and lowest in microscopic polyangiitis (2.2%, 95% CI 1.09-3.86), granulomatosis with polyangiitis (2.0%, 95% CI 1.20-3.01), cryoglobulinaemic vasculitis (1.9%, 95% CI 0.05-9.89), and IgA-vasculitis (Henoch-Schönlein) (0.4%, 95% CI 0.01-2.05). PSV patients had a 11.9% cumulative incidence of recurrent CVE during a 6-month follow-up period., Conclusion: CVEs affect a significant proportion of patients at time of PSV diagnosis, and the frequency varies widely among different vasculitis, being higher in Behçet's. Overall, CVE in PSV is not explained by traditional vascular risk factors and has a high risk of CVE recurrence., (© 2024. The Author(s).)

Objective: Somatic variants in UBA1 cause VEXAS, a recently described, systemic autoinflammatory disease. Research on VEXAS has largely focused on highly symptomatic patients. We sought to determine the prevalence of canonical, VEXAS-associated somatic variants and their disease penetrance in a diverse, unselected population., Methods: We analyzed clinical-grade whole genome sequencing data from 245,368 participants in the All of Us Research Program. We compared persons carrying a canonical VEXAS-associated somatic variant to age, sex, and ancestry matched controls across the domains of diagnoses, medications, and laboratory values., Results: 74 participants were identified who carry one VEXAS-defining somatic variant, UBA1 c.121A>C, p.Met41Leu. The variant allele fraction ranged from 4.5% to 33%. No other canonical VEXAS-associated variants were identified. Of the 74 carriers, 62 (84%) were women, 20 (27%) were African American, and 14 (19%) were American Admixed/Latino. There was no statistically significant association between case/control status and any VEXAS-associated diagnosis code, medication prescription, or laboratory value., Conclusion: We report the largest cohort to date of persons with the VEXAS-associated p.Met41Leu somatic variant. This cohort differed substantially from reported cohorts of patients with clinical VEXAS, having a higher proportion of persons who were young, female, and of diverse ancestry. Variant allele fractions were lower than reported in clinical VEXAS cohorts, and bioinformatic analysis detected no clinical manifestations of VEXAS. Thus, the UBA1 p.Met41Leu somatic variant displayed incomplete penetrance for VEXAS. Further study is needed to determine the natural history of VEXAS-associated somatic variants in the predisease phase., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Purpose: Little is known about the effectiveness of pharmacological cardioversion (PCV) with antazoline in comparison to flecainide. The aim of this study was to compare the effectiveness of antazoline in restoring sinus rhythm (SR) versus amiodarone, flecainide and propafenone in a group of emergency department (ED) patients., Materials/methods: This was a single-centre retrospective analysis of patient records from an ED in a large hospital in Poland. We analysed a total of 1878 patient records, divided based on the anti-arrhythmic drug (AAD) administered during PCV: antazoline (n ​= ​1080), antazoline ​+ ​β-blocker (n ​= ​479), amiodarone (n ​= ​129), flecainide (n ​= ​102), propafenone (n ​= ​88). Of the patients, 63.5 ​% were female (median 65 years, [19-100])., Results: The percentage of successful PCV was significantly higher in the antazoline group (84.3 ​%) than in the antazoline ​+ ​β-blocker (75.8 ​%, p ​= ​0.0001), propafenone (75.6 ​%, p ​= ​0.0364) and amiodarone (68.8 ​%, p ​< ​0.0001) groups. Post-hoc analysis revealed that patients who received PCV with antazoline, antazoline ​+ ​β-blocker, flecainide and propafenone had significantly shorter time to SR than those who received amiodarone (p ​< ​0.0001). Univariate regression analysis revealed that patients who underwent PCV with antazoline were almost twice as likely to return to SR compared to the other groups (p ​< ​0.0001, OR 1.81, 95 ​% CI 1.44-2.27)., Conclusions: This is the first study comparing the effectiveness of antazoline in PCV versus flecainide in addition to the previously studied amiodarone and propafenone. Our results indicate that antazoline is more effective in restoring SR than amiodarone, flecainide and propafenone. In addition, antazoline restored SR significantly faster than amiodarone or propafenone., (Copyright © 2024. Published by Elsevier B.V.)

Background: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy., Methods: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed., Findings: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%])., Interpretations: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE., Funding: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases., Competing Interests: Declaration of interests AS received consulting fees from AstraZeneca, AbbVie, GSK, Kezar Life Sciences, Eli Lilly, Bristol Myers Squibb and lecture fees from Astra Zeneca, Rheumatologic Dermatology Society, and Lupus Therapeutics. GC was a member of independent data monitoring boards of clinical trials by Roche and VERA therapeutics. BHR received consulting payments from Roche/Genentech, Aurinia, Novartis, Alexion, GSK, Kyverna, Kezar, HI-Bio, and Tome and served on the Board of Directors for NephroNet and the Scientific or Medical Advisory Board for the Lupus Foundation of America and Lupus Accelerating Breakthroughs Consortium/Lupus Research Alliance. RJL received support for the present manuscript as part of the Autoimmunity Centers of Excellence grant. DE received grants or contracts from the American College of Rheumatology and European Alliance of Associations for Rheumatology, NIH, GSK, and Exagen; royalties or licenses from UptoDate; consulting fees from Chugai, AbbVie, and Argenx; and lecture fees from GSK and Aurinia. JM is an employee of DAIT/NIAID, the sponsor and funding agency of this trial. CA received a grant or contract from GSK; consulting fees from GSK, AstraZeneca, Bristol Myers Squibb, and AbbVie; and served on a data safety monitoring or advisory board for Alumis. LKE serves as a consultant for Rho Federal Division. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE trial., Methods: Key efficacy outcomes were remission at week 26 and sustained remission at week 52. Additional outcomes included the Glucocorticoid Toxicity Index, estimated glomerular filtration rate, urinary albumin to creatinine ratio, health-related quality of life and safety., Results: Of the 330 patients who received study medication, 214 (64.8%) received rituximab (once weekly for 4 weeks), with a mean age of 59.8 years; 163 (76.2%) had renal vasculitis and 125 (58.4%) were newly diagnosed. Remission at week 26 and sustained remission at week 52 were achieved by 83/107 (77.6%) and 76/107 (71.0%) patients in the avacopan group and 81/107 (75.7%) and 60/107 (56.1%) in the prednisone taper group, respectively. The relapse rate, recovery of renal function, speed of reduction in albuminuria and glucocorticoid toxicity favoured the avacopan group. Serious adverse events occurred in 34.6% and 39.3% of patients in the avacopan and prednisone taper groups, respectively., Conclusions: These data suggest that in patients with ANCA-associated vasculitis receiving rituximab, efficacy of treatment with avacopan compared with a prednisone taper was similar at week 26 and greater at week 52, with a favourable safety profile. In addition, avacopan was associated with improved renal outcomes and lower glucocorticoid toxicity. These results demonstrate the efficacy and safety of avacopan in patients receiving background induction therapy with rituximab., Trial Registration Number: NCT02994927., Competing Interests: Competing interests: DG reports consultant fees from Amgen, ChemoCentryx (a wholly owned subsidiary of Amgen), Aurinia, Otsuka, Calliditas Therapeutics, and GlaxoSmithKline (GSK). AD reports consultant fees from Amgen, ChemoCentryx (a wholly owned subsidiary of Amgen), Novartis, Sanofi, AbbVie and GSK, grants from the Rheumatology Research Foundation, advisory board participation for Sanofi and GSK, honoraria and travel support for lectures from GSK, and a leadership role at the Vasculitis Foundation and Chicago Rheumatism Society. HY reports stocks from and was an employee of ChemoCentryx (a wholly owned subsidiary of Amgen) and Amgen. JS reports consultant fees from ChemoCentryx (a wholly owned subsidiary of Amgen). CS reports royalties from UpToDate and consultant fees from Amgen, Novartis, CSL Vifor, Lilly, Boehringer Ingelheim, Pfizer and Jannsen. DJ reports consultant fees from AstraZeneca, Boehringer Ingelheim, ChemoCentryx (a wholly owned subsidiary of Amgen), GSK, Novartis, Roche and CSL Vifor, and grant or research support from GSK and Roche. PM reports royalties from UpToDate, consultant fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ChemoCentryx (a wholly owned subsidiary of Amgen), Eicos, Electra, Forbius, Genentech/Roche, GSK, InflaRx, Neutrolis, Novartis, Sanofi and Takeda, support for travel to a scientific meeting from ChemoCentryx (a wholly owned subsidiary of Amgen), stock options from Kyverna and Sparrow, and grants to his institution from the National Institutes of Health, Food and Drug Administration, Vasculitis Foundation, American College of Rheumatology and EULAR., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)