A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study

Antonio Vitale, Antonella Insalaco, Paolo Sfriso, Giuseppe Lopalco, Giacomo Emmi, Marco Cattalini, Raffaele Manna, Rolando Cimaz, Roberta Priori, Rosaria Talarico, Stefano Gentileschi, Ginevra de Marchi, Micol Frassi, Romina Gallizzi, Alessandra Soriano, Maria Alessio, Daniele Cammelli, Maria C. Maggio, Renzo Marcolongo, Francesco La Torre, Claudia Fabiani, Serena Colafrancesco, Francesca Ricci, Paola Galozzi, Ombretta Viapiana, Elena Verrecchia, Manuela Pardeo, Lucia Cerrito, Elena Cavallaro, Alma N. Olivieri, Giuseppe Paolazzi, Gianfranco Vitiello, Armin Maier, Elena Silvestri, Chiara Stagnaro, Guido Valesini, Marta Mosca, Salvatore de Vita, Angela Tincani, Giovanni Lapadula, Bruno Frediani, Fabrizio De Benedetti, Florenzo Iannone, Leonardo Punzi, Carlo Salvarani, Mauro Galeazzi, Donato Rigante, Luca Cantarini

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis. Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults. Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016. Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0-2.0 mg/kg/day) among adults and 2-4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively). Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.