CO:06:3 | Clinical and laboratory markers for distinguishing VEXAS from Schnitzler's syndrome in male patients with skin involvement: insights from the International AIDA Network Registries

Valeria Caggiano¹, Jessica Sbalchiero¹, Micol Frassi², Andrea Hinojosa-Azaola³, Francesca Crisafulli², Franco Franceschini², Paolo Sfriso⁴, Sara Bindoli⁴, José Hernández-Rodríguez⁵, Henrique A. Mayrink Giardini⁶, Giuseppe Lopalco⁷, Florenzo Iannone⁷, Ombretta Viapiana⁸, Amato De Paulis⁹, Lorenzo Dagna¹⁰, Antonio Gidaro¹¹, Serena Bugatti¹², Matteo Piga¹³, Fabrizio Conti¹⁴, Rosetta Vitetta¹⁵, Cecilia Chighizola¹⁶, Marcello Govoni¹⁷, Giacomo Emmi¹⁸, Paola Triggianese¹⁹, Carmelo Gurnari¹⁹, Bruno Frediani¹, Claudia Fabiani¹, Luca Cantarini¹, Antonio Vitale¹, for the AIDA Network¹ | ¹Department of Medical Sciences, Surgery and Neurosciences, University of Siena; ²University of Brescia, Italy; ³Department of Immunology and Rheumatology, Mexico City, Mexico; ⁴Rheumatology Unit, University of Padova, Italy; ⁵Clinical Unit of Autoinflammatory Diseases, Hospital Clínic of Barcelona, Spain; ⁶Rheumatology Division, Universidade de São Paulo, Brazil; ⁷University of Bari; ⁸Rheumatology Unit, University and Azienda Ospedaliera Universitaria Integrata of Verona; ⁹University of Napoli "Federico II"; ¹⁰Università Vita-Salute San Raffaele, Milano; ¹¹Luigi Sacco Hospital, University of Milano; ¹²Università di Pavia; ¹³University and AOU of Cagliari; ¹⁴AOU Policlinico Umberto I, Sapienza University of Rome; ¹⁵Unit of Rheumatology, ASL Sant' Andrea Hospital, Vercelli; ¹⁶University of Milano; ¹⁷Azienda Ospedaliero-Universitaria S. Anna, Ferrara; ¹⁸University of Trieste; ¹⁹University of Rome-Tor Vergata, Rome, Italy.

Abstract

Background: VEXAS syndrome and Schnitzler’s disease are rare adult-onset autoinflammatory conditions that often present with overlapping clinical and laboratory features, particularly in the early stages. Both disorders are characterized by systemic inflammation, recurrent fever, cutaneous involvement, and elevated inflammatory markers. A common hallmark is the presence of urticarial rash, frequently associated with monoclonal gammopathy of undetermined significance (MGUS). Given these similarities—especially in older male patients—differential diagnosis may be particularly challenging, underscoring the need for specific clinical and laboratory markers to guide classification and management. As prognosis differs between the two entities, the present study was undertaken to identify the clinical and laboratory parameters that should raise suspicion for VEXAS syndrome among patients under evaluation for Schnitzler’s disease.

Methods: Data from patients with Schnitzler’s syndrome and VEXAS syndrome were obtained from the respective international AutoInflammatory Disease Alliance (AIDA) Network registries. Inclusion criteria for patients affected by VEXAS syndrome required the presence of a pathogenic or likely pathogenic mutation in the UBA1 gene. For patients with Schnitzler’s syndrome, the inclusion criteria required the fulfillment of Strasbourg diagnostic criteria. Male patients diagnosed with Schnitzler’s syndrome were compared to VEXAS patients who presented with urticarial skin manifestations. Clinical and laboratory features were analyzed using univariate and multivariable logistic regression models to identify variables associated with VEXAS syndrome.

Results. A total of 19 VEXAS patients and 18 patients with Schnitzler’s syndrome were enrolled. At univariate binary logistic regression, the diagnosis of VEXAS syndrome was associated with the age at disease onset (OR=1.08, 95% CI. 1.01-1.16, p=0.02), haemoglobin levels (OR=0.44, 95% CI. 0.26-0.77, p=0.003), the presence of anaemia (OR=13.9, 95% CI. 3.4-5.7, p=0.02), leucocytosis (OR=0.04, 95% CI. 0.06-0.22, p<0.001), lymphadenopathy (OR=7.8, 95% CI. 1.41-45.4, p=0.02), and thrombocytopenia (OR=13.5, 95% CI. 1.47-123.7, p=0.02). In the multivariable logistic regression analysis with the stepwise forward selection approach, the diagnosis of VEXAS syndrome was significantly associated with the age at disease onset (OR: 1.13, 95% CI: 1.02–1.30, p=0.04)), the presence of lymphadenopathy (OR: 67.49, 95% CI: 5.36–3284.89, p=0.007), and thrombocytopenia (OR: 12.02, 95% CI: 1.07–315.86, p=0.06). Figure 1 shows the probability of a VEXAS diagnosis based on age at disease onset, in the presence or absence of the other two variables.

Conclusions: The study provides a comparative framework that highlights specific clinical, and laboratory features distinguishing VEXAS syndrome from Schnitzler’s syndrome in male patients with cutaneous involvement. Specifically, patients with lymphadenopathy, thrombocytopenia, anemia, particularly in older age, and in the absence of leucocytosis, are more likely to be affected by VEXAS syndrome.

Keywords

• UBA1 mutation
• Skin manifestations
• Differential diagnosis