Silvia Peretti, Cosimo Bruni, Francesco Bonomi, Rossella De Angelis, Gianluigi Bajocchi, Dilia Giuggioli, Martina Orlandi, Giovanni Zanframundo, R. Foti, E. Visalli, Giovanna Cuomo, Alarico Ariani, Edoardo Rosato, Gemma Lepri, Francesco Girelli, Valeria Riccieri, Elisabetta Zanatta, Silvia Laura Bosello, Ilaria Cavazzana, Francesca Ingegnoli, Maria De Santis, Fabio Cacciapaglia, Giuseppe Murdaca, Giuseppina Abignano, Giorgio Pettiti, Alessandra Della Rossa, Maurizio Caminiti, Anna Iuliano, Giovanni Ciano, L. Beretta, Gianluca Bagnato, E. Lubrano, Ilenia De Andres, Luca Idolazzi, Marta Saracco, Cecilia Agnes, Corrado Campochiaro, Giacomo De Luca, Edoardo Cipolletta, M. Fornaro, F. Lumetti, Amelia Spinella, Luca Magnani, V. Codullo, Carlo Iandoli, A. Gigante, Greta Pellegrino, Erika Pigatto, Maria Grazia Lazzaroni, Enrico De Lorenzis, Gianna Mennillo, Marco Di Battista, Giuseppa Pagano Mariano, Federica Furini, Licia Vultaggio, Simone Parisi, Clara Lisa Peroni, Gerolamo Bianchi, Enrico Fusaro, Gian Domenico Sebastiani, Marcello Govoni, S. D’angelo, Franco Cozzi, Franco Franceschini, Serena Guiducci, Lorenzo DAGNA, Andrea Doria, Carlo Salvarani, Maria Antonietta D’Agostino, Florenzo Iannone, Marco Matucci-Cerinic, Clodoveo Ferri, Silvia Bellando Randone
Background: The sequence and temporal relationship between Raynaud's phenomenon (RP) and the first non-Raynaud's sign/symptom (NRP) in systemic sclerosis (SSc) have been partially investigated. Objectives: To evaluate whether the mode and ages of clinical onset are associated with disease endotype and survival in SSc. Design: We included SSc patients from the Systemic sclerosis Progression INvestiGation registry of the Italian Society of Rheumatology (SPRING-SIR) registry in a cohort study, with post hoc cross-sectional and longitudinal analysis. Methods: Patients were grouped based on age-RP and age-NRP quartiles. Additionally, categories were defined based on mode of onset: RP group-RP onset at least 1 year before NRP; Simultaneous group-RP onset within the same year of NRP; NRP group-RP onset after at least 1 year after NRP. Comparisons were made using Chi-square and ANOVA tests. Logistic, linear, and multinomial regression models were applied to assess associations, while Kaplan-Meier curves and Cox regression were used to assess mortality. Results: A total of 1748 patients were eligible: 682 (39.0%) in the RP group, 1026 (58.8%) in the simultaneous group, and 39 (2.2%) in the NRP group. A higher prevalence of anti-centromere antibodies was found In the RP group, while the simultaneous group had more diffuse cutaneous SSc (dcSSc), anti-topoisomerase-I antibodies, and higher Rodnan's skin score (mRSS). The NRP group presented higher prevalence of pulmonary arterial hypertension. On logistic regression, the simultaneous group was associated with a higher prevalence of dcSSc compared to the RP group (odds ratio, 1.491, 95% confidence interval (CI): 1.032-2.154). Younger age at RP onset was associated with lower systolic pulmonary artery pressure and mRSS. In 943 patients with available follow-up (median 24 months), the simultaneous group had higher mortality compared to the RP group (hazard ratio, 1.975, 95% CI: 1.002-3.893). Conclusion: The timing of RP and NRP onset may help define SSc endotype and survival. Patients with simultaneous RP-NRP onset have more severe disease features and higher mortality risk, emphasizing the relevance of onset timing in disease stratification.