Systemic Sclerosis Association with Malignancy

Abstract

The association of systemic sclerosis (SSc) and cancer is well known from several decades suggesting common genetic and environmental risk factors involved in the development of both diseases. Immunosuppressive drugs widely used in SSc may increase the risk of cancer occurrence and different SSc clinical and serological features identify patients at major risk to develop malignancy. In this context, among serological features, presence of anti-RNA polymerase III and anti-topoisomerase I autoantibodies seems to increase cancer frequency in SSc patients (particularly lung and breast cancers). Lung fibrosis and a long standing SSc pulmonary involvement have been largely proposed as lung cancer risk factors, and the exposure to cyclophosphamide and an upper gastrointestinal involvement have been traditionally linked to bladder and oesophagus cancers, respectively. Furthermore, immune checkpoint inhibitors used for cancer therapy can induce immune-related adverse events, which are more frequent and severe in patients with pre-existing autoimmune diseases such as SSc. The strong association between SSc and cancer occurrence steers clinicians to carefully survey SSc patients performing periodical malignancy screening. In the present review, the most relevant bilateral relationships between SSc and cancer will be addressed.

Keywords: Autoantibodies; Cancer; Malignancy; Risk factors; Systemic sclerosis.

Fig. 1

Inhibitory immune checkpoints targeting. Multiple approaches are available to target immune checkpoints for the treatment of autoimmune disease or cancer. Shown on the right example of immune checkpoints inhibitors (ICIs) approved for the treatment of cancer (e.g., antibodies against PD-1, PD-L1 and CTLA-4) and additional emergent checkpoint-blocking approaches (e.g., antibodies against TIGIT and VISTA). These antibodies negatively regulate the inhibitory immune receptors keeping the immune response active and promoting kill of tumor cells. On the left some specific examples of inhibitory receptors that have been targeted in preclinical and clinical studies: soluble inhibitory-receptor-Fc fusion protein (CTLA-4-Fc and TIGIT-Fc ) ligand-Fc fusion protein (VISTA-Fc), bispecific antibodies (PDI-CD3). Contrary to the principle of cancer immune theraphy with ICIs, these methods keep the immune response off improving the course of the autoimmune diseases. mAB, monoclonal antibody; PD-1, programmed dealth protein 1; PD-L1, PD-1 ligand; CTLA-4, cytotoxic T-lymphocyte antigen 4; TGIT, T cell immunureceptor with Ig and ITIM domains; VISTA, V-type immuniglobulin domain-containing suppressor of T-cell activation, VISTA-R, VISTA receptor, Image created with BioRender.com