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

## TL;DR

Recurrent fevers in VEXAS syndrome are linked to severe organ problems, higher mortality, and partial treatment responses, suggesting fevers could guide treatment strategies.

## Contribution

This study identifies febrile episodes as a marker for severe disease and treatment outcomes in VEXAS syndrome using Bayesian analysis.

## Key findings

- Recurrent fever episodes are strongly associated with mortality and major organ involvement in VEXAS patients.
- Fever episodes correlate with partial treatment responses to standard therapies but high treatment failure with anti-interleukin-1 agents.
- Patients with fevers show negligible complete response or treatment failure probabilities.

## Abstract

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.

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.

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%].

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.