Cancer in connective tissue disease

Abstract

The association between cancer and autoimmunity is well-recognized, as represented by the increased incidence of cancer among patients with systemic autoimmune diseases; however, the underlying mechanisms remain only partially understood. On the one hand, malignancy may trigger a breakdown of immune tolerance in predisposed individuals, as autoimmune syndromes often emerge shortly after cancer diagnosis, suggesting that tumor antigens might initiate an autoimmune response. However, by involving persistent responses and the creation of a pro-inflammatory environment, the chronic immune activation characteristic of autoimmunity may promote oncogenesis. This scenario is further complicated by the use of immunosuppressive therapies for autoimmune conditions, which, as seen in transplant immunology, are associated with a higher risk of cancer, although data in rheumatology have not yielded definitive conclusions. Connective tissue diseases include systemic lupus erythematosus, primary Sjögren syndrome, idiopathic inflammatory myopathies, systemic sclerosis, mixed connective tissue disease, and undifferentiated forms. These conditions have been variably associated with an increased risk of cancer, both at the time of disease onset and in patients with long-standing autoimmune conditions, providing a paradigm for investigating this complex interplay. Despite recent progress, many unmet needs remain that warrant further research.

Keywords: autoantibodies; autoimmunity; connective tissue disease (CTD); immunology; malignancy.

Figure 1

Cancer as both an environmental trigger and pathological consequence of autoimmunity in the paradigm of CTDs. The pathogenesis of autoimmune diseases involves a hypothetical environmental trigger that induces immune system response. In genetically predisposed individuals, this leads to an aberrant immune activation, which becomes dysregulated and persists over time, resulting in chronic inflammation. The chronic inflammatory milieu causes tissue damage due to ongoing inflammation but synchronously provides a precancerous condition (i.e., an environment that predisposes to the development of cancerous lesions). From this perspective, CTD are at a crossroads between cancer and autoimmunity. On the one hand, strong evidence supports the role of cancer as a trigger of autoimmune responses (as seen in cancer-associated myositis and scleroderma). However, the disease itself increases the risk of malignancies, particularly in tissues undergoing chronic inflammatory remodeling (such as the lung in SSc and lymphopoiesis in pSS).

Figure 2

The interplay between cancer and SSc. Some forms of SSc can be regarded as cancer-associated (or paraneoplastic) scleroderma, in which the putative etiological role of malignancy is supposed to trigger the onset of autoimmunity in predisposed individuals (a). Cancer can also occur in longstanding SSc, particularly at specific sites and is associated with the selection of risk factors, phenotypes, and disease complications (b). Immunosuppressive and cytotoxic treatments are commonly adopted to treat SSc-related complications; however, the putative role of such therapies remains elusive (c). CTP-neg, ‘CTP-negative’ patients; dcSSc, diffuse cutaneous SSc; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension; pHI, primary heart involvement.