Dear Editor,

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus, lower gastrointestinal tract, lungs, heart, and kidneys). Systemic sclerosis is associated with an increased risk of malignancy. Risk factors predisposing an SSc patient to development of malignancy are not well defined, and the pathogenic basis of the association is yet to be explained. Some autoantibodies have been associated with a close temporal relationship to cancer. The absence of malignancy-screening guidelines tailored to SSc patients raises the importance of the need for more studies on the association between SSc and cancer.

In this retrospective cohort report, we determined the prevalence of cancer in SSc and studied the association between SSc-specific and SSc-associated autoantibodies in two centers with autoimmune diseases outpatient clinics. We conducted a retrospective cohort study by including patients diagnosed with SSc followed from 1980 to 2020 fulfilling the 2013 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SSc criteria. Demographic features and clinical and immunological characteristics were retrieved. The primary outcome was SSc-associated cancer, defined as cancer occurring within 2, 5, and 10 years of first non-Raynaud SSc manifestation. The exposure was defined by the presence of SSc-specific/SSc-associated autoantibodies, including anti-centromere (ACA), anti-topoisomerase I (Scl70), anti-RNA polymerase III (anti-RNA pol III), anti-fibrillarin, anti-Th/To, anti-PM-Scl, anti-Ku, anti-TIF1g, and anti-Ro52. Descriptive analysis was used to compare clinical characteristics of subjects with cancer to those without cancer. Univariate logistic regression was used to compare the odds of SSc-associated cancer between the autoantibody subgroups.

Out of 123 SSc subjects, 35 (28%) had a history of cancer following their SSc diagnosis. Mean age was 65.9 (59–70) years, 67% were female, and 88% had a smoking history. Median time between cancer and disease onset was 5.33 (3.2–8.5) years. Among patients with cancer, 20 (57%) were diagnosed in the first 2 years after SSc onset, 8 (29%) were diagnosed after 2–5 years, and 7 (26%) were diagnosed 5–10 years after SSc onset. The most frequent malignancies were breast cancer (n = 13), lung cancer (n = 6), gastrointestinal cancer (n = 5), prostatic cancer (n = 4), hematological (n = 3) cancers, cervical/uterine cancers (n = 2), and non-melanoma skin cancer (n = 2). Patients with cancer were more likely to be Scl70 positive (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.03–6.3, p 0.04), anti-TIF1g positive (OR 19.5, 95% CI 5.6–68.3, p 0.001), and anti-RNA pol III positive (OR 10.9, 95% CI 1.08–109.3, p 0.04); have a history of smoking (OR 7.24, 95% CI 2.6–197, p 0.001) and myositis (OR 5.2, 95% CI 2.06–13.2, p 0.005); and older age at SSc onset (61.9 vs. 57 years, p 0.04). Breast cancer was more frequent in anti-TIF1g (OR 3.75, 95% CI 1.8–17.5) and anti-RNA pol-III (OR 7.14 95% CI 1.56–90.8) subgroups. Results from logistic regression analysis for the risk of cancer within 2, 2–5, and 5–10 years of SSc onset are summarized in Table 1. The risk of SSc-associated cancer was significantly increased among anti-TIF1g-positive subjects at 5 years after SSc onset (OR 2.1, 95% CI 1.45–9.94, p 0.04) and among anti-RNA-pol III-positive subjects at 2 years after SSc onset (OR 3.5, 95% CI 1.2–51.4, p 0.02).

Table 1 Logistic regression analysis for the risk of cancer within 2, 5, and 10 years of SSc onset according to antibody positivity
Full size table

The incidence of malignancy in SSc varies between studies. It can coincide with the diagnosis or may be a consequence of treatment for it or another condition [1,2,3]. In addition, malignancy has been described with both diffuse and limited SSc [4]. Many reports state that more women than men have been reported, with a mean age of 58 years [5]. The average duration of follow-up from SSc onset to development of cancer is typically 5–9 years [6]. The development of lung cancer in patients with SSc with lung involvement is very frequent, with some studies reporting an odds ratio of 5.9 for lung cancer [7]. The second most frequently diagnosed entity is breast cancer, and there are reports of other common malignancies such as gastrointestinal and hematological cancer [8, 9]. Our data coincide with most of the literature, as the majority of patients with a cancer history were women, with 5.33 years between disease onset and cancer diagnosis. Breast cancer was also very frequent; however, lung and hematological cancers were detected in only 6 and 3 patients in our series, respectively. We recognize that this study has limitations due to it is retrospective nature, requiring revision of patients’ clinical history, and missing data.

In conclusion, anti-Scl70, anti-TIF1g, and anti-RNA pol III were associated with an increased risk of cancer. Breast cancer was the most frequent type of cancer. Smoking, myositis, and an older age at SSc onset were more frequent in subjects with cancer. Autoantibodies should be taken into account in cancer screening. Larger studies are needed to define the risk of SSc-associated cancer in different autoantibody subgroups.