Systemic Sclerosis Linked to Dramatic Rise in Lung Cancer Risk

Women with systemic sclerosis faced a nearly 10-fold increase in lung cancer risk compared with the general population in a long-running inception cohort—almost double the risk seen in men with the same disease, according to new data published in Clinical and Experimental Rheumatology.¹

A Cancer Signal Rheumatologists Could Not Ignore

Population-based cohort studies have linked systemic sclerosis (SSc) to an elevated risk of lung cancer, but a Mendelian randomization analysis had cast doubt on whether the association was truly causal rather than a byproduct of shared risk factors such as smoking or underlying interstitial lung disease. For rheumatologists managing a disease already marked by skin fibrosis, vasculopathy, and progressive organ involvement, resolving that uncertainty mattered for how aggressively to pursue cancer screening in these patients.²

Researchers in Greece set out to clarify the picture by analyzing lung cancer incidence in an academic inception cohort of patients followed from the time of SSc onset, then placing those findings in context with a systematic review and meta-analysis of previously published data.¹

The cohort included patients evaluated within 12 months of SSc onset between January 1995 and December 2020, with regular follow-up through December 2024—among the longer observation windows reported for this question. Clinical manifestations, laboratory parameters, treatments, and comorbidities were recorded prospectively throughout. Age-standardized incidence ratios (SIRs) of lung cancer were calculated using Global Cancer Observatory reference data, and Cox proportional hazards models identified clinical predictors of lung cancer development.

To place the single-center findings in a broader context, the authors conducted a systematic literature search on SSc and cancer risk and performed a meta-analysis of lung cancer SIRs pooled across 17 eligible studies.

A Risk That Nearly Doubles in Women

Among 180 patients followed for 2110 person-years, lung cancer was diagnosed in 12, a mean (SD) of 10.2 (5.9) years after SSc onset. The age-SIR for the full cohort was 5.1 (95% CI, 4.7-5.4), rising to 9.5 (95% CI, 8.7-10.3) in women and settling at 3.8 (95% CI, 3.5-4.1) in men. Diffuse cutaneous subtype (HR, 4.22; 95% CI, 1.03-17.35) and a smoking history (HR, 4.49; 95% CI, 1.14-17.69) were both associated with higher lung cancer risk, whereas digital ulcers were inversely associated with risk (HR, 0.13; 95% CI, 0.03-0.63). The meta-analysis of 17 studies, encompassing 27,563 patients with SSc, produced a pooled age-SIR of 3.85 (95% CI, 2.63-5.63), reinforcing the cohort's signal at a population level.

“Long-term follow-up data from an SSc inception cohort indicate a 5-fold increased lung cancer risk in SSc, nearly doubled among female patients,” the researchers wrote, adding that further studies are warranted to inform screening strategies specific to this population.

A Modest Case Count Despite Decades of Follow-Up

Only 12 incident lung cancers were observed in the primary cohort, a small absolute number that widens the confidence intervals around subgroup estimates, including the sex-stratified SIRs. The inverse association with digital ulcers, in particular, warrants cautious interpretation given the limited event count behind it.

Heterogeneity across the 17 studies pooled in the meta-analysis, differing in population, follow-up duration, and case ascertainment, also means the pooled estimate should be read as a general signal rather than a precise risk figure applicable to any single patient population.

The findings give rheumatologists and payers a clearer rationale for discussing lung cancer screening with patients who have diffuse cutaneous SSc or a smoking history, and report being of female sex, particularly since SSc-associated interstitial lung disease already prompts regular pulmonary surveillance in many practices. Coordinating that existing imaging infrastructure with formal lung cancer screening criteria, the authors suggested, could help translate this risk signal into earlier detection.

References

1. Makris A, Poulia V, Bournia VK, et al. Lung cancer risk in systemic sclerosis: data from an inception cohort and meta-analysis of published studies. Clin Exp Rheumatol. 2026;44(8):1570-1581. doi:10.55563/clinexprheumatol/by5ndi
2. National Institute of Arthritis and Musculoskeletal and Skin Diseases. Scleroderma. NIH. Accessed October 1, 2026. https://www.niams.nih.gov/health-topics/scleroderma