Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer

Abstract

Objectives: Recent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma. Investigating cancer risk in these biologically relevant subsets may provide an opportunity to develop personalised cancer screening guidelines. In this study, we examined cancer risk in distinct serologic and phenotypic scleroderma subsets and compared estimates with the general population.

Methods: Patients in the Johns Hopkins Scleroderma Center observational cohort were studied. Overall and site-specific cancer incidence was calculated in distinct autoantibody and scleroderma phenotypic subsets, and compared with the Surveillance, Epidemiology and End Results registry, a representative sample of the US population.

Results: 2383 patients with scleroderma contributing 37 686 person-years were studied. 205 patients (8.6%) had a diagnosis of cancer. Within 3 years of scleroderma onset, cancer risk was increased in patients with RNA polymerase III autoantibodies (antipol; standardised incidence ratio (SIR) 2.84, 95% CI 1.89 to 4.10) and those lacking centromere, topoisomerase-1 and pol antibodies (SIR 1.83, 95% CI 1.10 to 2.86). Among antipol-positive patients, cancer-specific risk may vary by scleroderma subtype; those with diffuse scleroderma had an increased breast cancer risk, whereas those with limited scleroderma had high lung cancer risk. In contrast, patients with anticentromere antibodies had a lower risk of cancer during follow-up (SIR 0.59, 95% CI 0.44 to 0.76).

Conclusions: Autoantibody specificity and disease subtype are biologically meaningful filters that may inform cancer risk stratification in patients with scleroderma. Future research testing the value of targeted cancer screening strategies in patients with scleroderma is needed.

Keywords: autoantibodies; epidemiology; systemic sclerosis.

Figure 1.. Risk of all cancers over time.

In each graph, the x-axis reflects time from scleroderma onset (defined as time zero). Top and middle rows, each time window represents a 6-year period (±3 years); for example, data plotted at time zero reflects cancer risk within ±3 years of scleroderma onset. The number at risk for each time window is denoted at the bottom of the graph. Top row, the observed number of cancer cases (blue) is presented in comparison with the number of cancer cases that are expected based on SEER data (red). Middle row, the ratio between the observed and expected cancer cases is presented as a standardized incidence ratio (SIR) along with its 95% confidence interval. Values of 1 denote a cancer risk equivalent to that of the background population. Bottom row, the cumulative incidence of cancer among scleroderma patients (solid blue line) starting at 3 years before scleroderma onset is presented with 95% confidence intervals (shaded blue region). Red lines represent the expected cumulative incidence of cancer based on SEER data for the general population. Scleroderma patients with anti-centromere antibodies appear to have a decreased risk of cancer over time. Scleroderma patients with pol III antibodies and the CTP-Negative group have an increased risk of cancer that is prominent at scleroderma onset. The cumulative incidence of cancer is significantly higher than that observed in the general population among patients with pol III autoantibodies.

Figure 2.. Risk of breast cancers over time.

In each graph, the x-axis reflects time from scleroderma onset (defined as time zero). Top and middle rows, each time window represents a 6-year period (±3 years); for example, data plotted at time zero reflects breast cancer risk within ±3 years of scleroderma onset. Top row, the observed number of breast cancer cases (blue) is presented in comparison with the number of breast cancer cases that are expected based on SEER data (red). Middle row, the ratio between the observed and expected breast cancer cases is presented as a standardized incidence ratio (SIR) along with its 95% confidence interval. Values of 1 denote a breast cancer risk equivalent to that of the background population. Bottom row, the cumulative incidence of breast cancer among scleroderma patients (solid blue line) starting at 3 years before scleroderma onset is presented with 95% confidence intervals (shaded blue region). Red lines represent the expected cumulative incidence of breast cancer based on SEER data for the general population. Patients with topo and cenp antibodies do not have an increased risk of breast cancer. Scleroderma patients with pol III antibodies and the CTP-Negative group have an increased risk of breast cancer that is prominent at scleroderma onset. The cumulative incidence of breast cancer is significantly higher than that observed in the general population among patients with pol III autoantibodies.

Figure 3.. Risk of lung cancers over time.

In each graph, the x-axis reflects time from scleroderma onset (defined as time zero). Top and middle rows, each time window represents a 6-year period (±3 years); for example, data plotted at time zero reflects lung cancer risk within ±3 years of scleroderma onset. Top row, the observed number of lung cancer cases (blue) is presented in comparison with the number of lung cancer cases that are expected based on SEER data (red). Middle row, the ratio between the observed and expected lung cancer cases is presented as a standardized incidence ratio (SIR) along with its 95% confidence interval. Values of 1 denote a lung cancer risk equivalent to that of the background population. Bottom row, the cumulative incidence of lung cancer among scleroderma patients (solid blue line) starting at 3 years before scleroderma onset is presented with 95% confidence intervals (shaded blue region). Red lines represent the expected cumulative incidence of lung cancer based on SEER data for the general population. Scleroderma patients with pol III antibodies may have an increased risk of lung cancer at the time of scleroderma onset.