Cancer and Scleroderma

Abstract

Individuals with scleroderma have an increased risk of cancer compared with the general population. This heightened risk may be from chronic inflammation and tissue damage, malignant transformation provoked by immunosuppressive therapies, or a common inciting factor. In unique subsets of patients with scleroderma, there is a close temporal relationship between the onset of cancer and scleroderma, suggesting cancer-induced autoimmunity. This article discusses the potential mechanistic links between cancer and scleroderma, the serologic and clinical risk factors associated with increased cancer risk in patients with scleroderma, and implications for cancer screening.

Keywords: Autoantibodies; Cancer screening; Epidemiology; Malignancy; Scleroderma.

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 anti-POLR3 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 anti-POLR3 antibodies. Adapted with permission. From Igusa T, Hummers LK, Visvanathan K, et al. Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer. Ann Rheum Dis. 22018;77(8): 1179–1186; with permission.

Figure 2.. Model of cancer-induced autoimmunity.

Transformation of normal cells (1) may result in gene expression patterns that resemble immature cells involved in tissue healing (2). Occasionally, autoantigens become mutated (3); these are not driver mutations, and not all cancer cells have them. The first immune response is directed against the mutated form of the antigen (4), and may spread to the wild-type version (5). Immune effector cells directed against the mutant (depicted in red) delete exclusively cancer cells containing the mutation (6). Immune effector cells directed against the wild type (depicted in blue) delete cancer cells without the mutation and also cross-react with the patient’s own tissues (particularly immature cells expressing high levels of antigen, found in damaged/repairing tissue) (7). Once autoimmunity has been initiated, the disease is self-propagating. Immature cells (expressing high antigen levels) that repair the immune-mediated injury can themselves become the targets of the immune response, sustaining an ongoing cycle of damage/repair that provides the antigen source that fuels the autoimmune response. From Shah AA, Casciola-Rosen L, Rosen A. Review: cancer-induced autoimmunity in the rheumatic diseases. Arthritis Rheumatol. 2015;67(2):317–326.; with permission.