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.
Keywords: Raynaud’s phenomenon; disease onset; non-Raynaud’s symptoms; risk assessment; systemic sclerosis.
How systemic sclerosis starts impacts how the disease will behave Systemic sclerosis (SSc) is a rare autoimmune disease that affects the skin and internal organs. In most cases the disease starts with Raynaud’s phenomenon (RP), a discolouring of the fingers in reaction to cold temperatures; some other patients may experience different symptoms first, such as joint pain, skin changes or shortness of breath. Understanding which symptom appears first, and at what age, may help doctors identify patients who are more likely to develop severe disease. This study included 1,748 SSc patients enrolled in the Italian SPRING-SIR registry, divided patients into three groups: those who first developed RP (RP group), those who developed RP and other symptoms in the same year (Simultaneous), and those who developed non-RP symptoms first (NRP group). We found that patients in the RP group were younger at disease onset and often had milder disease. Patients in the Simultaneous group were more likely to develop diffuse skin disease, lung complications, and had a higher risk of death. Patients in the NRPgroup were rare but often had aggressive involvement of heart and lung. Overall, our results show that the timing of RP and non-RP symptoms can help predict disease course and survival in SSc. These findings may help doctors recognize higher-risk patients earlier and provide closer monitoring and tailored treatments.
© The Author(s), 2026.