Arthritis Rheumatol. 2026 Aug 28. doi: 10.1002/art.70303. Online ahead of print.
ABSTRACT
BACKGROUND: Cancer represents a major cause of mortality in systemic sclerosis (SSc). Established risk factors are limited to specific subsets, particularly early diffuse anti-RNA polymerase III (POLR3)-positive disease, needing further exploration.
METHODS: We performed a nested case-control study within EUSTAR: cases were SSc patients developing cancer at any timepoint; controls were cancer-free SSc matched for age and disease duration. Malignancies were classified as synchronous to SSc onset (±3 years), subsequent (>3 years after), or previous (>3 years before). Clinical, serological, treatments associations, and survival were analyzed.
RESULTS: 454 SSc patients with cancer (29% synchronous, 51% subsequent, 20% previous), and 454 controls were identified. Mean age was 55±13 years, disease duration 5±2 years; 88% were female, 27.5% diffuse SSc; 30.5% had interstitial lung disease (ILD), 32% anti-topoisomerase, 10% anti-POLR3. Synchronous cancers were associated with anti-POLR3 (OR 2.06, 95%CI 1.13-3.69), U1RNP (OR 3.56, 1.03-12.3), smoking (OR 1.57, 1.01-2.44), but negatively with digital ulcers (OR 0.55, 0.31-0.93). Calcinosis was inversely associated with subsequent cancers (OR 0.42, 0.17-0.93). Breast cancer showed time-dependent associations with anti-POLR3 and anti-PM/Scl; lung cancer was mainly subsequent and associated with ILD (OR 2.00, 1.12-3.54), anti-topoisomerase (OR 2.61, 1.38-5.04), and smoking. Cancers occurred more frequently in cyclophosphamide-treated patients. Malignancy worsened overall survival, particularly when subsequent. Radiation therapy did not impact mortality or new-onset ILD.
CONCLUSIONS: Cancer timing and site identify distinct clinical-serological associations in SSc, with different prognostic implications. As cancers diagnosed during follow-up are major determinants of mortality, our findings inform the implementation of stratified cancer surveillance in SSc.
PMID:42663235 | DOI:10.1002/art.70303