Understanding disease progression and malignancies
—
The Very Early Diagnosis of Systemic Sclerosis (VEDOSS) criteria identify red flags as puffy fingers, abnormal nailfold capillaroscopy, and specific autoantibodies in patients with Raynaud’s phenomenon as a very early disease stage where patients do fulfil the classification criteria. New work presented at the 2025 congress of EULAR – The European Alliance of Associations for Rheumatology – looks at key predictors and outcomes – including a new composite score to help understand disease progression and common drivers of mortality, and achieve earlier and more robust indicators.

The VEDOSS project has previously shown that 70% of patients with Raynaud’s phenomenon and at least one red flag – systemic sclerosis (SSc)-specific antibodies, puffy fingers, or an SSc pattern on nailfold capillaroscopy –will fulfil the 2013 ACR/EULAR SSc criteria within 5 years.¹ However, it is acknowledged that although essential for classification, fulfilment of the criteria does not necessarily reflect clinically relevant disease progression. Instead, significant early events such as onset of digital ulcers, skin fibrosis, or interstitial lung disease (ILD), may represent more robust indicators of disease progression in people with very early SSc.

Stefano Di Donato and colleagues aimed to evaluate progression of VEDOSS patients in order to develop the first clinically significant disease-onset outcome in a time-to-event analysis. These data were presented in Barcelona at the annual EULAR congress. The work included 442 VEDOSS patients who did not fulfil the 2013 criteria and had none of the clinical endpoints at baseline. Progression was defined as the first occurrence of one of the following within 5 years: first digital ulcer or gangrene, modified Rodnan skin score (mRSS) ≥1, scleroderma renal crisis (SRC), new ILD on CT scan, new pulmonary arterial hypertension, new synovitis, left ventricular ejection fraction <50%, or forced vital capacity (FVC) or diffusing capacity for carbon monoxide (DLCO) below 80% of predicted – key markers of functional outcomes. ACR/EULAR criteria progression was also reported, represented by reaching the classification threshold.

During follow up, 51.1% of patients developed one of the clinically significant events, with a cumulative progression probability of 11.1% at 12 months, rising to 41.5% and 65.6% at 36 and 60 months, respectively. The most frequent events were mRSS ≥1 (31.5%), DLCO decline (29.8%), and first digital ulcer or gangrene (15.1%). Overall, almost two-thirds of patients experienced this first event before fulfilling the classification criteria. The authors stress that the progression to clinical signs in people with VEDOSS red flags is a testament to the validity of very early diagnosis – and highlights the opportunity for very early intervention to minimise the impact of SSc on patients’ lives.

Early disease identification and intervention is important, because SSc has high mortality – partly due to heart and lung manifestations, but also associated comorbidities – with a significantly higher cancer risk for individuals with an SSc diagnosis. In particular, haematological malignancies are common, with an elevated risk up to 150% compared with individuals without SSc. Previous studies have suggested that these malignancies begin in the years following SSc diagnosis, but there is a lack of robust, detailed and contemporary data. Work presented by Karin Gunnarsson details findings from a set of population-based healthcare registers in Sweden that help shed some light.

The researchers found 1,720 individuals with SSc and matched them by sex, age, and residential area to up to 10 comparators from the general population, and then looked for haematological malignancies. Overall, first-time haematological malignancies were identified in 1.6% of individuals with SSc compared to 0.9% without – giving a crude incidence rate of 2.3 versus 1.2 per 1000 person-years, with raised hazard ratios for lymphoid, plasma cell, myeloid, and B cell malignancies. The risk differences were highest in men and in individuals whose SSc developed at a young age (18–49 years).

Source
Di Donato S, et al. Clinically significant events are better early indicators of disease progression in Systemic Sclerosis beyond ACR/EULAR criteria: insights from the VEDOSS EUSTAR cohort. Presented at EULAR 2025; OP0214. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B3801.

Gunnarsson K, et al. Hematological malignancies in systemic sclerosis, a population-based nationwide register study. Presented at EULAR 2025; OP0221. Ann Rheum Dis 2025; DOI: 10.1136/annrheumdis-2025-eular.B444.

References
1. Bellando-Randone S, et al. Progression of patients with Raynaud's phenomenon to systemic sclerosis: a five-year analysis of the European Scleroderma Trial and Research group multicentre, longitudinal registry study for Very Early Diagnosis of Systemic Sclerosis (VEDOSS). Lancet Rheumatol 2021;3(12):e834–43. DOI: 10.1016/S2665-9913(21)00244-7.