Recurrent fever and association with severe organ involvement, mortality and treatment outcomes in VEXAS syndrome: data from the AIDA Network

Introduction Recurrent febrile episodes account for one of the most frequent symptoms observed in Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome and a key target for therapeutic intervention. Therefore, this study aims at investigating the association between recurrent febrile episodes and specific clinical manifestations, mortality and response to treatment. Methods Data were obtained from the international AutoInflammatory Disease Alliance (AIDA) Network registry and analyzed using a Bayesian statistical approach. Posterior probabilities [P(β)] were calculated to assess the likelihood that fever was associated with clinical, laboratory, genetic, and therapeutic features. Results In total, 87 VEXAS patients were enrolled, 65 (74.7%) of whom suffered from recurrent fever episodes. Fever episodes showed a significant association with patients’ mortality [P(β): 99.41%], as well as with major inflammatory organ involvement, including cardiac [P(β): 99.99%], lung [P(β): 99.98%], and gastrointestinal [P(β): 97.5%] involvement. The occurrence of recurrent fever episodes was associated with a negligible probability of both complete response and treatment failure [P(β) <2.5%], instead favoring a partial response [P(β) >97.5%] to conventional disease modifying anti-rheumatic drugs, Janus Kinases inhibitors, and tocilizumab. For temperatures exceeding 40 °C, using anti-interleukin-1 agents was associated with a high probability of treatment failure [P(β): 99.3%]. Conclusions febrile episodes are associated with more severe pattern of organ involvement and, accordingly, to death. Furthermore, febrile episodes could correlate with differential therapeutic responsiveness, thereby potentially serving as a valuable marker to guide the treatment strategies in VEXAS patients.

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Journal
Frontiers in Immunology
Published
2026-03-13
DOI
https://doi.org/10.3389/fimmu.2026.1753412
Primary Topic
Otitis Media and Relapsing Polychondritis
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article
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article

Recurrent fever and association with severe organ involvement, mortality and treatment outcomes in VEXAS syndrome: data from the AIDA Network

Bruno Frediani, Álvaro González-García, Valeria Caggiano, Antonio Vitale et al.
Frontiers in Immunology
Otitis Media and Relapsing Polychondritis
article

Recurrent fever and association with severe organ involvement, mortality and treatment outcomes in VEXAS syndrome: data from the AIDA Network

Bruno Frediani, Álvaro González-García, Valeria Caggiano, Antonio Vitale, Francesca Crisafulli, Alessandro Tomelleri, Alberto Balistreri, Federica Di Cianni, M. Piga, A De Paulis, Alessandra Milanesi, Adriana Soto-Peleteiro, A. Cauli, Carmelo Gurnari, AN Tufan, Chiara Cardamone, Riccardo Bixio, Alicia Callisto, Mark Beecher, Pravin Hissaria, Micol Frassi, Mehmet Ali Ergün, Francesco Ferro, A. Mayo-Juanatey, Jessica Sbalchiero, Henrique A. Mayrink Giardini, Serena Bugatti, Jiram Torres-Ruiz, Verónica Gómez-Caverzaschi, Vincenzo Sorrentino, Samuele Rizzo, Maria Chiara Cuccaro, Alessandra Renieri, Sara Bindoli, Eduardo Martín-Nares, Paola Triggianese, Corrado Campochiaro, Anna Nowakowska-Plaza, Olga Araújo, Marcella Prete, Claudia Fabiani, Monica Bocchia, Vito Racanelli, Guillermo Ruiz-Irastorza, Andrea Hinojosa-Azaola, Ombretta Viapiana, Ilaria Cavazzana, Luca Cantarini, Fabrizio Conti, Guillermo Arturo Guaracha-Basañez, Lorenzo Dagna, Paolo Sfriso, Ewa Wiesik-Szewczyk, José Hernández-Rodríguez, Rosetta Vitetta, Rosaria Talarico, Giuseppe Lopalco
article en

Abstract

Introduction Recurrent febrile episodes account for one of the most frequent symptoms observed in Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome and a key target for therapeutic intervention. Therefore, this study aims at investigating the association between recurrent febrile episodes and specific clinical manifestations, mortality and response to treatment. Methods Data were obtained from the international AutoInflammatory Disease Alliance (AIDA) Network registry and analyzed using a Bayesian statistical approach. Posterior probabilities [P(β)] were calculated to assess the likelihood that fever was associated with clinical, laboratory, genetic, and therapeutic features. Results In total, 87 VEXAS patients were enrolled, 65 (74.7%) of whom suffered from recurrent fever episodes. Fever episodes showed a significant association with patients’ mortality [P(β): 99.41%], as well as with major inflammatory organ involvement, including cardiac [P(β): 99.99%], lung [P(β): 99.98%], and gastrointestinal [P(β): 97.5%] involvement. The occurrence of recurrent fever episodes was associated with a negligible probability of both complete response and treatment failure [P(β) <2.5%], instead favoring a partial response [P(β) >97.5%] to conventional disease modifying anti-rheumatic drugs, Janus Kinases inhibitors, and tocilizumab. For temperatures exceeding 40 °C, using anti-interleukin-1 agents was associated with a high probability of treatment failure [P(β): 99.3%]. Conclusions febrile episodes are associated with more severe pattern of organ involvement and, accordingly, to death. Furthermore, febrile episodes could correlate with differential therapeutic responsiveness, thereby potentially serving as a valuable marker to guide the treatment strategies in VEXAS patients.

Frontiers in ImmunologyVol. 17
University of Siena (IT), University of Pisa (IT), University of Rome Tor Vergata (IT), National Academy of Medicine (US), Cleveland Clinic (US), Royal Adelaide Hospital (AU), University of Maryland Medical System (US), Vita-Salute San Raffaele University (IT), University of the Basque Country (ES), University of Trento (IT), Instituto Cajal (ES), University of Pavia (IT), Policlinico Umberto I (IT), Cancer Institute (WIA) (IN), World Allergy Organization (US), Ospedale Santa Chiara (IT), BioCruces Health research Institute (ES), ASL Roma (IT), Azienda Ospedaliera Universitaria Integrata Verona (IT), Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (MX), Ospedale Sacro Cuore Don Calabria (IT), Federico II University Hospital (IT), Gazi Hastanesi (TR), Azienda Ospedaliero-Universitaria Cagliari (IT), Hospital Universitario Doctor Peset (ES), IRCCS Ospedale San Raffaele (IT), Ospedali Riuniti San Giovanni di Dio e Ruggi d'Aragona (IT), Azienda Ospedaliera Universitaria Senese (IT), ERN GUARD-Heart (NL), Immune Regulation (United Kingdom) (GB), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Azienda Sanitaria Locale Roma 3 (IT), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Hospital Universitario Ramón y Cajal (ES), University of Bari Aldo Moro (IT), Gazi University (TR)
Università degli Studi di Padova, Università degli Studi di Pavia, Università degli Studi di Brescia
Good health and well-being
Openalex Percentile: Top 22%
Otitis Media and Relapsing Polychondritis
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