Examination of autoantibody status and clinical features associated with cancer risk and cancer-associated scleroderma

Abstract

Objective: We previously reported a contemporaneous onset of cancer and scleroderma in patients with anti-RNA polymerase III antibodies, and we identified a biologic link between cancer and scleroderma. This investigation was designed to further evaluate whether autoantibody status and other characteristics are associated with cancer and a clustering of cancer with scleroderma onset.

Methods: Logistic regression analysis was performed to assess the relationship of 2 outcomes, cancer (model 1) and a short (±2 years) cancer-scleroderma interval (model 2), with autoantibody status and scleroderma covariates.

Results: Of 1,044 scleroderma patients, 168 (16.1%) had cancer. In the adjusted model 1, only older age at scleroderma onset (odds ratio 1.04 [95% confidence interval 1.02-1.05]) and white race (odds ratio 2.71 [95% confidence interval 1.22-6.04]) were significantly associated with an increased overall risk of cancer. In the adjusted model 2, only anti-RNA polymerase III positivity (odds ratio 5.08 [95% confidence interval 1.60-16.1]) and older age at scleroderma onset (odds ratio 1.04 [95% confidence interval 1.00-1.08]) were significantly associated with a short cancer-scleroderma interval. While anti-RNA polymerase III positivity was associated with a short cancer-scleroderma interval independent of age at scleroderma onset, the cancer-scleroderma interval shortened with older age at scleroderma onset in other antibody groups (Spearman's correlation P < 0.05), particularly among patients with anti-topoisomerase I antibodies and patients who were negative for anticentromere, anti-topoisomerase I, and anti-RNA polymerase III antibodies.

Conclusion: Increased age at scleroderma onset is strongly associated with cancer risk overall. While anti-RNA polymerase III status is an independent marker of coincident cancer and scleroderma at any age, a clustering of cancer with scleroderma is also seen in patients with anti-topoisomerase I and other autoantibody specificities who develop scleroderma at older ages.

Figure 1. The relationship between age at cancer diagnosis and age at scleroderma onset

A) The red line in each scatterplot denotes perfect concordance between age of cancer diagnosis and age of scleroderma onset, i.e. where the cancer-scleroderma interval equals zero. While a small number of patients with anti-centromere antibodies have a short cancer-scleroderma interval, the vast majority of patients have wide intervals often with scleroderma preceding cancer by many years. In contrast, patients with anti-RNA polymerase III have an almost universal short cancer-scleroderma interval, as shown by the majority of patients clustering along the red line. Among topo positive patients, the cancer-scleroderma interval shortens with increasing age at scleroderma onset. The “Other” subgroup shows features of the other 3 known antibody subsets; there is a increased clustering of cancer with scleroderma among patients with an older age at scleroderma onset, but patients with wider intervals are also present. This subgroup likely consists of patients targeting multiple autoantibody specificities, and this may account for the varied patterns observed. B) A kernel density function illustrates the distributions of age at scleroderma onset and age at cancer diagnosis. Again the distributions of age at scleroderma onset and age at cancer diagnosis are strikingly similar for the pol positive patients, with significant overlap also noted in the topo and “Other” patient subgroups.