Clinical and Laboratory Markers to Distinguish VEXAS from Schnitzler's Syndrome: data from the AIDA Network Registries

Valeria Caggiano¹Jessica Sbalchiero¹Micol Frassi²Eduardo Martin-Nares³Andrea Hinojosa-Azaola³Mariusz Sikora⁴Karina Jahnz-Różyk⁴Francesca Crisafulli²Franco Franceschini²Paolo Airò²Guillermo Arturo Guaracha-Basañez³José Jiram Torres-Ruiz³Paolo Sfriso⁵Sara Bindoli⁵Chiara Baggio⁵José Hernández-Rodríguez⁶Veronica Gomez-Caverzaschi⁶Gerard Espinosa⁶Henrique A Mayrink Giardini⁷Rafael Alves Cordeiro⁷Andrés González-García⁸Mercedes Peña-Rodríguez⁸Giuseppe Lopalco⁹Florenzo Iannone⁹Ombretta Viapiana¹⁰Abdurrahman Tufan¹¹Hamit Kucuk¹¹Pravin Hissaria¹²Mark Beecher¹²Amato De Paulis¹³Ilaria Mormile¹³Lorenzo Dagna¹⁴Corrado Campochiaro¹⁴Antonio Gidaro¹⁵Leyla La Cava¹⁵Serena Bugatti¹⁶Alessandra Milanesi¹⁶Guillermo Ruiz-Irastorza¹⁷Matteo Piga¹⁸Fabrizio Conti¹⁹Paolo Moscato²⁰Daniela Opris-Belinski²¹Rosetta Vitetta²²Cecilia Chighizola¹⁵Andreas Recke²³Fernando Tornero-Romero²⁴Marcella Prete⁹Marcello Govoni²⁵Giacomo Emmi²⁶Perla Ayumi Kawakami-Campos³Paola Triggianese²⁷Carmelo Gurnari²⁷Gaafar Ragab²⁸Alberto Balistreri²⁹Marcin Ziętkiewicz³⁰Ewa Wiesik-Szewczyk³⁰Bruno Frediani²⁹Claudia Fabiani²⁹Anna Sicuranza²⁹Monica Bocchia²⁹Luca Cantarini^1*Antonio Vitale²⁹

• ¹University of Siena, Siena, Italy
• ²Universita degli Studi di Brescia, Brescia, Italy
• ³Instituto Politecnico Nacional Escuela Nacional de Ciencias Biologicas, Mexico City, Mexico
• ⁴Military Institute of Medicine, National Research Institute, Warsaw, Poland
• ⁵Universita degli Studi di Padova, Padua, Italy
• ⁶Universitat de Barcelona, Barcelona, Spain
• ⁷Universidade de Sao Paulo, São Paulo, Brazil
• ⁸Hospital Universitario Ramon y Cajal, Madrid, Spain
• ⁹Universita degli Studi di Bari Aldo Moro, Bari, Italy
• ¹⁰Universita degli Studi di Verona, Verona, Italy
• ¹¹Gazi Universitesi, Ankara, Türkiye
• ¹²Royal Adelaide Hospital, Adelaide, Australia
• ¹³Universita degli Studi di Napoli Federico II, Naples, Italy
• ¹⁴Universita Vita Salute San Raffaele, Milan, Italy
• ¹⁵Universita degli Studi di Milano, Milan, Italy
• ¹⁶Universita di Pavia, Pavia, Italy
• ¹⁷Escuela Oficial de Idiomas de Barakaldo, Barakaldo, Spain
• ¹⁸Universita degli Studi di Cagliari, Cagliari, Italy
• ¹⁹Universita degli Studi di Roma La Sapienza, Rome, Italy
• ²⁰Universita degli Studi di Salerno, Fisciano, Italy
• ²¹Universitatea de Medicina si Farmacie Carol Davila din Bucuresti Facultatea de Farmacie, Bucharest, Romania
• ²²Presidio Ospedaliero Sant'Andrea di Vercelli, Vercelli, Italy
• ²³Universitatsklinikum Schleswig-Holstein Campus Lubeck, Lübeck, Germany
• ²⁴Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain
• ²⁵Universita degli Studi di Ferrara, Ferrara, Italy
• ²⁶Universita degli Studi di Trieste, Trieste, Italy
• ²⁷Universita degli Studi di Roma Tor Vergata, Rome, Italy
• ²⁸Cairo University, Giza, Egypt
• ²⁹Universita degli Studi di Siena, Siena, Italy
• ³⁰Wojskowy Instytut Medyczny - Panstwowy Instytut Badawczy, Warsaw, Poland

Background: A substantial overlap in demographic, clinical, and laboratory features can complicate the differential diagnosis between Schnitzler’s syndrome and VEXAS syndrome. The present study was undertaken to identify clinical and laboratory parameters that should raise suspicion for VEXAS syndrome among patients previously diagnosed with, or under evaluation for, Schnitzler’s syndrome. Methods: Data from male-only patients with Schnitzler’s syndrome or VEXAS syndrome were obtained from international AIDA Network registries. Subjects with Schnitzler’s syndrome were compared to VEXAS patients with urticarial skin manifestations resembling cutaneous features typically observed in Schnitzler’s 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), 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) and the presence of lymphadenopathy (OR: 67.49, 95% CI: 5.36–3284.89, p=0.007), while thrombocytopenia showed a trend toward statistical significance (OR: 12.02, 95% CI: 1.07–315.86, p = 0.06). Conclusions: Patients with lymphadenopathy, thrombocytopenia, anemia, particularly in older age and in the absence of leucocytosis, are more likely to be affected by VEXAS syndrome rather than Schnitzler’s syndrome.