Step forward in early recognition of systemic sclerosis: data from the Leiden CCISS cohort

**Background:** Systemic sclerosis (SSc) is a heterogeneous autoimmune disease with variable clinical course. Early recognition is critical for timely intervention, but diagnostic delays have been reported. The Leiden Combined Care in Systemic Sclerosis (CCISS) cohort, initiated in 2009, provides standardized screening for organ involvement. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival have changed.

**Methods:** 643 SSc patients fulfilling ACR/EULAR 2013 criteria were included and categorized into three groups by cohort-entry year: (1) 2010–2013 (n=229, 36%), (2) 2014–2017 (n=207, 32%), and (3) 2018–2021 (n=207, 32%). Disease duration was assessed using three definitions: months from cohort entry to (a) physician-confirmed diagnosis, (b) onset of Raynaud's phenomenon (RP), and (c) first non-RP symptom. Organ involvement included interstitial lung disease (ILD) on HRCT, digital ulcers (DU), diffuse cutaneous SSc (dcSSc), and cardiac involvement. Eight-year survival from disease onset was analyzed using Kaplan-Meier methods and Cox proportional hazard models, stratified by sex and autoantibody status (ACA, ATA).

**Key Results:** Mean age at cohort entry was 55 years (SD 14); 80% were female; 95% were ANA-positive; 43% ACA-positive; 21% ATA-positive. Disease duration at cohort entry decreased significantly over time: median RP duration fell from 120 months (IQR 44–240) in 2010–2013 to 68 months (IQR 21–210) in 2018–2021 (p=0.010); non-RP duration decreased from 46 months (IQR 16–127) to 17 months (IQR 6–55) (p<0.001); diagnosis duration decreased from 22 months (IQR 5–99) to 4 months (IQR 0–18) (p<0.001). Disease duration was consistently longer in females than males. The proportion of patients presenting with DU decreased from 20% to 12% (p=0.036). ILD on HRCT decreased from 43% to 31% (p=0.033). Clinically meaningful ILD (HRCT + FVC <80%) showed a downward trend from 12% to 6% (p=0.092). ACA positivity increased from 38% to 49% (p=0.091). Overall 8-year survival was 82% (95% CI 76% to 87%). Eight-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Survival showed an upward trend over time, with the 2018–2021 group reaching 85% (95% CI 52% to 96%). In Cox regression, male sex (HR 4.7, 95% CI 2.3 to 9.5) and older age (HR 1.1, 95% CI 1.05 to 1.1) were associated with increased mortality risk; per cohort-entry year, there was a non-significant downward trend (HR 0.93, 95% CI 0.81 to 1.1).

**Clinical Implications:** The observed decrease in disease duration at cohort entry suggests improved early recognition of SSc over the past decade, potentially opening a window of opportunity for early intervention before irreversible organ damage occurs. The reduction in DU and clinically meaningful ILD at presentation may reflect both earlier diagnosis and improved disease awareness. However, the persistent sex disparity—longer diagnostic delay in females but higher mortality in males—underscores the need for sex-specific strategies in screening, treatment, and follow-up. The findings support continued efforts to identify SSc patients earlier, particularly through screening of Raynaud's phenomenon, and highlight the importance of stratifying clinical trial design and analysis by sex.