Benjamin de Valence de Minardiere1, Marion Delaune2, Yann Nguyen3, Vincent Jachiet4, Mael Heiblig5, Alexis Jean6, Pierrick Henneton7, stanislas Riescher-tuczkiewicz8, Philippe Guilpain7, Hervé Lobbes9, Guillaume Le Guenno10, Nicolas Schleinitz11, Valentin Lacombe12, Vincent Langlois13, Roderau Outh14, Julien Vinit15, Jean-Philippe Martellosio16, Paul Decker17, Alexandre Vlakos18, Thomas Moulinet19, Yannick Dieudonne20, Adrien Bigot21, Louis Terriou22, Bertrand De Maleprade23, Guillaume Denis24, Jonathan Broner25, Marie Kostine26, Sébastien Humbert27, Benjamin Terrier28, Sophie Georgin-Lavialle29, Olivier Fain30, Arsène Mekinian1, Marjolaine MORGAND1, Thibault Comont2 and Jerome Hadjadj1, 1Department of Internal Medicine, Hôpital Saint-Antoine, AP-HP, Paris, France, 2Toulouse University Hospital, Toulouse, France, 3Department of Internal Medicine, Hôpital Beaujon, AP-HP, Clichy, France., Montmorency, France, 4Service de médecine interne et Inflammation-Immunopathology-Biotherapy Department (DMU i3), Sorbonne Université, AP-HP, Hôpital Saint Antoine, Paris, France, 5Hematology, Hospices Civils de Lyon, Lyon-Sud Hospital, Pierre-Bénite, France, 6Internal Medicine Department, Bordeaux University, Faculty of Medicine, Bordeaux University Hospital, Bordeaux, France, 7CHU Montpellier, Montpellier, France, 8CHU de Nantes, Nantes, France, 9CHU de Clermont-Ferrand, Clermont-Ferrand, France, 10Internal Medicine Department, Clermont-Ferrand University, Faculty of Medicine, Estaing University Hospital, Clermont-Ferrand, France, 11Aix Marseille university, AP-HM, Marseille, France, 12Internal Medicine Department, Anger Hospital, Clermont-Ferrand, France, 13Service de Médecine Interne, Hôpital Jacques Monod, Le Havre, France, 14Internal Medicine Department, Perpignan Hospital Center, Perpignan, France, 15Service de Médecine Interne, CH William Morey, Chalon sur Saône, France., Chalon sur Saône, France, 16Service de médecine interne, maladies infectieuses et tropicales, CHU de Poitiers, Poitiers, France, 17Nancy hospital, France, Nancy, France, 18Vesoul Hospital, Vesoul, France, 19Department of Internal Medicine, Centre hospitalier universitaire de Nancy, Nancy, France, 20Department of Clinical Immunology and Internal Medicine, National Reference Centre for Systemic Autoimmune Diseases (CNR RESO), Strasbourg University Hospital, Strasbourg, France, 21Internal Medicine Department, Tours University, Faculty of Medicine, Tours University Hospital, Tours, France, 22Service de Médecine Interne et Immunologie Clinique, CHU Lille, Lille, France, 23Rouen hospital, France, Rouen, France, 24Service d'hématologie, CH de Rochefort, Rochefort, France, 25CHU de Nimes, Nimes, France, 26Bordeaux University Hospital, Bordeaux, France, 27Besançon University Hospital, Besançon, France, 28Department of Internal Medicine, Hôpital Cochin, AP-HP, Paris, France, 29AP-HP, Tenon hospital, Paris, France, 30Hopital SAINT ANTOINE APHP, Paris, France
Background/Purpose: VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) syndrome is an autoinflammatory monogenic disease caused by inactivating somatic mutations in the UBA1 gene and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations. Its management is not consensual but often include biologic DMARDs or azacytidine in case of association with myelodysplastic syndrome. Prognosis appears to be poor, with substantial morbidity and mortality mainly caused by infection. The aim of this study was to describe the spectrum of infectious complications and their risk factors in VEXAS patients.
Methods: Retrospective multicenter study including patients with genetically proven VEXAS syndrome, with at least one episode of severe infection (defined as an infection leading to hospitalization and/or intravenous infectious treatments and/or death). These patients were compared to a cohort of 50 VEXAS patients without severe infection after at least one year of follow-up since diagnosis. Risk factors of infections were assessed with multivariate Cox proportional hazard ratios models.
Results: Seventy-four patients (99% male, median [IQR] age at VEXAS onset of 68 [63-75] years) with 133 severe infections were included. Infections occurred despite anti-infective prophylaxis in 46% of cases. The main immunosuppressive drugs received at the time of infection were JAK inhibitors (29%), biologics (21%) and azacitidine (11%), while 16% of infections occurred without treatment (no immunosuppressant or corticosteroids ≤ 10 mg/d). Most frequent infection localizations were the lung (59%), skin (10%) and urinary tract (9%). The most commonly found infectious agents were SARS-CoV-2, Legionella pneumophila and Pneumocystis jivoreci in 28%, 21% and 19% of pulmonary infections, respectively (figure 1).Invasive fungal infections accounted for 11% of all infections. Nearly 20% of pulmonary infections occurred in the absence of treatment with a high prevalence of L. pneumophila (42%) and P. jivoreci (17%) infections.
In multivariate analysis, factors significantly associated with severe infection were p.Met41Val mutation (figure 2) (HR 2.44 [1.05-5.63], p=0.037), age at symptom onset >75 years (HR 1.91 [1.05-3.47], p=0.034) and arthralgia (HR 2.03 [1.16-3.56], p=0.013) whereas leukopenia was a protective factor (HR 0.58 [0.34-0.99], p=0.046). Among treated patients, cumulative infection rate was significantly higher with JAK inhibitors (multivariate HR 3.90 [1.78-8.55], p=0.001) compared to biologic DMARDs and azacitidine, with a median time to infection of 12 months (figure 3). After a median follow-up of 4.4 [2.5–7.7] years, 27 (36%) patients died including 15 (56%) due to severe infection.
Conclusion: VEXAS syndrome is associated with a high incidence of severe infections especially in patients carrying the p.Met41Val mutation. The high frequency of atypical infections such as legionellosis and invasive fungal infections in patient without immunosuppressive treatment might suggest an intrinsic immunodeficiency of the disease. JAK inhibitors, used as first-line treatment, are particularly at risk of severe infections occurring early after initiation.
Figure 1: Distribution of infectious agents in pulmonary infections
Figure 2: Kaplan-Meier curves for infection-free survival according to the type of UBA1 mutation
Figure 3: Cumulative incidence of severe infections according to the type of treatment received
B. de Valence de Minardiere: None; M. Delaune: None; Y. Nguyen: None; V. Jachiet: None; M. Heiblig: None; A. Jean: None; P. Henneton: None; s. Riescher-tuczkiewicz: None; P. Guilpain: None; H. Lobbes: None; G. Le Guenno: None; N. Schleinitz: CSL behring, 1, Eusapharma, 6, GSK, 6; V. Lacombe: None; V. Langlois: None; R. Outh: None; J. Vinit: None; J. Martellosio: None; P. Decker: None; A. Vlakos: None; T. Moulinet: None; Y. Dieudonne: None; A. Bigot: None; L. Terriou: None; B. De Maleprade: None; G. Denis: None; J. Broner: None; M. Kostine: None; S. Humbert: None; B. Terrier: AstraZeneca, 5, CSL Vifor, 2, GlaxoSmithKlein(GSK), 2; S. Georgin-Lavialle: None; O. Fain: None; A. Mekinian: None; M. MORGAND: None; T. Comont: None; J. Hadjadj: None.
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