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Introduction Hand involvement is a hallmark of Systemic Sclerosis (SSc) and a major driver of disability and reduced quality of life. This study aimed to investigate the impact of cutaneous, vascular, and musculoskeletal involvement on hand function by assessing clinical, radiographic, and ultrasonographic features in a real-life population of patients from three centers.Material and Methods Patients were enrolled in a multicenter, cross-sectional study. Clinical history was obtained through patient interviews and review of medical records. Clinical examination, as well as ultrasound (US) and radiography (RX) of the hands and wrists were performed. PROs included the Cochin Hand Function Scale (CHFS), a validated measure of hand-related activity limitations based on difficulty performing daily tasks. Analogue data were obtained from an external validation cohort. Both separate and pooled cohorts’ analyses were conducted.Results A total of 140 consecutive patients (106 women and 34 men) were enrolled (73 from the Paris-Pavia Cohort and 67 from the Rennes Validation Cohort). Median (IQR) CHFS score was 6 [1.5; 20.5] in the original cohort and 10 [2.5; 24.5] in the validation cohort. In both univariate and multivariate analyses, CHFS scores showed a statistically significant correlation with the modified Rodnan skin score (mRSS) (p < 0.001) and with US-detected tenosynovitis (p < 0.01). A trend was also observed for US-detected tenosynovitis with a sclerosing pattern and for the presence of calcinosis, with statistically significant correlations in univariate analysis (p = 0.01 and p = 0.02, respectively), but borderline in multivariate analysis (p = 0.06 and p = 0.055, respectively). No association with autoantibodies status or pattern of distribution of skin fibrosis (diffuse or limited) was observed.Conclusions Hand function impairment affects SSc patients across all disease subsets. Our findings support the multifactorial origin of hand function impairment in SSc patients, with contributions from cutaneous (mRSS), vascular (calcinosis), and musculoskeletal (US-detected tenosynovitis) involvement. Skin fibrosis and tenosynovitis detected by US emerged as the most significant variables associated with hand disability, as measured by the CHFS. These results suggest a critical role for hand US in the routine management of SSc patients. Further, larger prospective studies are warranted to assess the prognostic value of baseline and follow-up hand and wrist US in predicting hand damage and guiding both treatment strategies and outcome measures in clinical trials.Abstract P.313 Table 1Association of CHFS scores with clinical, radiographic and ultrasonographic features in Univariate and multivariate analyses across all cohorts