Early clinical events flag systemic sclerosis earlier than the classification criteria

More than half of at-risk patients progress to clinically significant Systemic Sclerosis (SSc) manifestations within 5 years, often before meeting ACR/EULAR classification criteria. Moreover, the risk of progression was significantly associated with anti-centromere and anti-topoisomerase I antibodies.

In the very early stages of SSc, certain signs and symptoms may already be present [1]. “95% of patients go through a phase before organ complications, characterised mostly by Raynaud’s phenomenon and puffy fingers,” explained Dr Stefano Di Donato (University of Leeds, United Kingdom) [2]. Thus, his research team evaluated the development of clinically significant events in individuals fulfilling Very Early Diagnosis of Systemic Sclerosis (VEDOSS) red flags—Raynaud’s phenomenon with puffy fingers, nailfold capillaroscopy changes, or SSc-specific autoantibodies—yet not meeting the 2013 ACR/EULAR classification criteria.

In this analysis, 442 patients were followed for a median of 26 months. Over half (51.1%) developed clinically significant disease manifestations, with a cumulative progression probability of 11.2% at 12 months, 41.6% at 36 months, and 65.7% at 60 months. The most frequent first events were skin involvement defined as modified Rodnan skin score ≥1 (31.5%), diffusing capacity of the lungs for carbon monoxide decline (29.8%), digital ulcers (15.1%), and synovitis (12.9%).

Risk of event-based progression within 60 months was significantly associated with anti-centromere antibodies (HR 3.70; P<0.001), anti-topoisomerase I antibodies (HR 2.63; P=0.006), presence of giant capillaries on nailfold capillaroscopy (HR 1.88; P=0.004), baseline age (HR 1.03 per year; P<0.001), and oesophageal symptoms (HR 1.66; P=0.038).

These findings underscore the importance of clinical monitoring for early disease signs, as nearly two-thirds of clinically progressing patients would not have been captured using standard classification criteria alone. Such early progression highlights an urgent need for refined criteria or complementary tools in identifying SSc in its earliest, potentially modifiable phase.

Clinically significant events may serve as more practical markers of early SSc progression than traditional classification thresholds. “The idea would be to perform interventions that freeze SSc at an early stage where there is still no organ involvement,” Dr Di Donato concluded.

1. Van den Hoogen F, et Ann Rheum Dis 2013;72:1747-55.
2. Di Donato Clinically significant events are better early indicators of disease progression in Systemic Sclerosis beyond ACR/EULAR criteria: insights from the VEDOSS EUSTAR cohort. OP0214, EULAR 2025, 11–14 June, Barcelona, Spain.

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Posted on 8 August 20258 August 2025