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Introduction Although anti-centromere autoantibodies (ACA) are among the most prevalent in systemic sclerosis (SSc), the clinical phenotype of ACA-positive patients—including protective factors against major organ involvements—remains poorly defined. This lack of understanding may lead to potential over-monitoring and overtreatment in low-risk patients.Material and Methods Study was approved as EUSTAR CP155.ACA-positive SSc patients fulfilling the 2013 ACR/EULAR criteria were identified from the EUSTAR database. Data at initial entry into the EUSTAR database were analyzed, and patients were categorized by disease duration: T1 (0–1 year), T2 (2–5 years), T3 (6–10 years), and T4 (>=10 years). The following major organ involvements were explored: interstitial lung disease (ILD); pulmonary hypertension (PH); heart involvement (HI); scleroderma renal crisis (SRC); gastrointestinal (GIT) , musculoskeletal involvement (MUS) and digital ulcers (DUs), see figure 1. The prevalence of patients without organ involvement was calculated for the entire cohort and across the four subgroups. Multivariable logistic regression models using stepwise selection based on Akaike Information Criterion (AIC), ROC, and AUC analyses were used to determine factors associated with major organ involvements.Results Among 7,723 ACA-positive patients (39.6% of the EUSTAR cohort), GIT involvement was most frequent (67.6%), while the majority of patients had never experienced DUs (68.8%, 2.721/3.953), MUS involvement (72.6%, 5.214/7.185), ILD (77.1%,2.470/3.204), or HI (70.1%,4.427/6.319). ( Figure 2A). Organ complications increased with disease duration, rising 2–3 fold from T1 to T4. Yet, nearly 50% of patients remained free of major organ involvement (excluding GIT) after 10 years of disease (T4) (figure 2B).Multivariable logistic regression analyses identified the strongest factors associated with the absence of major organ involvements (figure 3): age of onset<=50 years for PH and HI, female gender and %pFVC>=80 for ILD, %pDLCO>=80 for PAH, lcSSc for DUs and SRC, absence of telangiectasias for PH and GIT, early/active capillaroscopy pattern and female gender for DUs, normal CRP levels for lung, heart and MUS involvement. In general key protective factors for the absence of major organ involvement were: lcSSc and preserved lung function tests (figure 4).Conclusions Contrary to general assumptions, ACA-positive patients are not uniformly protected from disease progression. Our study identified key protective factors for different major organ involvements. Validating these ‘green flags’ can support individualized care, guide monitoring, and inform trial enrollment.Abstract OC.26 Figure 1Definition of disease related complicationsAbstract OC.26 Figure 2Demegraphie and distrse features in the whole cohert of anti ceromere Se poaitive satiets ot thai dost incdusion in the EUSTARt datiboss (Panel A). Poaalance of organ ivolwenent in the 4 cohorts of ans-centromere positive 59c patiens angregoned according to their disoase dustion (Panel B)Abstract OC.26 Figure 3Multivariable regression analysis of the factors associated with the absence of disease-related organ damageAbstract OC.26 Figure 4General protective factors for the absence of major organ involvement in ACA-Positive systemic sclerosis: a multivariate logistic regression analysis