Introduction

Autoimmune conditions have long been associated with an increased risk of malignancy. While the pathogenic mechanisms underlying an increased cancer risk are not fully understood, the link between cancer and autoimmunity is likely dynamic and bidirectional in nature . Multiple immune and inflammatory pathways may activate tumorigenesis, and data suggest that active, inflammatory rheumatic disease may contribute to cancer initiation and promotion. Similarly, antitumor immune responses that limit tumor growth may become cross-reactive with self-tissues resulting in autoimmunity. Given the difficulty in measuring relatively rare outcomes such as cancer in the rheumatic diseases, large longitudinal epidemiological studies are valuable for understanding the relationships between malignancy and autoimmunity. In this review, we discuss recent data on cancer in the rheumatic diseases and suggest a research agenda to address several gaps in our current knowledge base.

Mechanisms that may explain the increased risk of cancer in the autoimmune rheumatic diseases

An increased risk of cancer has been demonstrated across the broad spectrum of autoimmune rheumatic diseases. While it is beyond the scope of this article to review cancer risk in detail for all of the rheumatic diseases, Table 1 describes the magnitude of risk and specific tumor sites of concern based on the recently published meta-analyses for select diseases. A wide array of cancer types is observed, with an increased risk of both solid organ and hematologic malignancies.

The relationship between cancer and the autoimmune rheumatic diseases is complex with many potential mechanisms linking the two disease states ( Table 2 ). Malignancy may develop secondary to the rheumatic disease and its therapies. For instance, it has been proposed that chronic inflammation and tissue damage may stimulate cytokines and chemokines that further the development of malignancies through multiple mechanisms, including inducing DNA damage, inactivating tumor suppressor genes, stimulating enhanced cellular growth and survival, triggering angiogenesis, and enhancing invasion . Within the rheumatic diseases, a model of inflammation-induced cancer may be particularly important in systemic lupus erythematosus (SLE; detailed later), but other data also suggest the relevance of this mechanism in Sjogren’s syndrome, rheumatoid arthritis (RA), and systemic sclerosis (SSc). In Sjogren’s syndrome, studies have demonstrated that salivary gland enlargement, hypocomplementemia, neutropenia, cryoglobulinemia, splenomegaly, lymphadenopathy, longer disease duration, and lymphoid organization in labial salivary gland biopsies at diagnosis are predictive of lymphoma risk . In RA, an increased risk of cancer and greater cancer mortality have been observed in patients who have elevated inflammatory markers . In addition, a case–control study examining RA patients with lymphoma compared to RA controls suggested that long-term corticosteroid therapy, and administration of intra-articular steroids used to treat acute flares, were associated with a lower risk of lymphoma . In SSc, multiple studies have demonstrated an increased risk of lung cancer in patients with interstitial lung disease, although this has not been found consistently across all studies . However, data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which enrolled >65,000 individuals, have demonstrated that baseline pulmonary scar is associated with future ipsilateral lung cancer, suggesting that this mechanism may also apply for patients with SSc .

In addition to disease activity and damage, antirheumatic disease therapies may increase the risk of subsequent malignancy. In particular, cyclophosphamide is an alkylating agent that causes cross-linking of DNA strands, thereby impeding cell division and resulting in apoptosis . Acrolein, a metabolite of cyclophosphamide, is excreted by the kidneys and concentrated in the urine. This is considered to cause bladder toxicity including cystitis and cancer. Additional data on cancer risk with cyclophosphamide use are mixed due to varying diseases under study, route of drug administration, dosing, and duration of therapy . However, studies have demonstrated that higher cumulative doses, an oral route of administration, and current or former smoking all associate with a higher risk of subsequent cancer . Data on cancer risk with mycophenolate mofetil is less clear as most of the available data stem from the transplant literature where patients are on multiple concomitant immunosuppressive therapies . Some studies suggest an increased risk of nonmelanoma skin cancers and lymphomas, whereas others do not. Recent data suggest that primary central nervous system (CNS) lymphoma risk may be increased in particular with mycophenolate use . The risk of nonmelanoma skin cancer is likely increased in patients with RA who are treated with tumor necrosis factor (TNF) inhibitors, and some studies suggest that the risk may also be increased for melanoma . Annual total body skin examination and counseling about sunscreen use is recommended in this patient population.

Immune dysregulation from the disease or immunosuppressive therapies could also influence the ability to clear oncogenic infections. In a large study of 576 SLE patients, the risk of virus-associated cancers was elevated (SIR 2.9), and this was noted in particular with human papillomavirus (HPV)-associated malignancies including anal cancer (SIR 26.9), vaginal/vulvar cancer (SIR 9.1), cervical dysplasia/CIS (SIR 1.8), and nonmelanoma skin cancers (SIR 2.0) . The risk was also elevated for other potential virally associated cancers, including liver cancer (hepatitis B and C viruses), bladder cancer (polyoma virus), and non-Hodgkin’s lymphoma (NHL; Epstein–Barr virus, EBV) .

While most studies investigating the link between rheumatic diseases and cancer have focused on malignancies developing after rheumatic disease onset, it is important to note that some patients develop clinical manifestations of autoimmunity shortly after a diagnosis of cancer. This raises the question of whether anticancer therapies increase the risk of developing autoimmune diseases. For example, bleomycin and gemcitabine have been reported as potential triggers of skin sclerosis and development or exacerbation of Raynaud’s phenomenon and ischemic digits . Chemotherapeutic agents may cause direct vascular toxicity and neurotoxicity, thus potentially resulting in endothelial dysfunction and aberrant sympathetic arterial vasoconstriction . Arthralgias, myalgias, lupus or RA-like syndromes, and reactive arthritis may also develop with various anticancer therapies . Increasingly, a wide array of immunotherapies, such as interleukin (IL)-2 therapy used for malignant melanoma and renal cell carcinoma, antitumor T cell infusions, cancer vaccines, and immune checkpoint inhibitors, are being used for cancer treatment. These agents prime and amplify the host immune response to destroy neoplastic cells, and of the development of new autoimmune diseases and disease exacerbations in patients with previously quiescent rheumatic disease after exposure to immunotherapy agents has been reported . As these drugs are increasingly being studied in clinical trials, it is likely that rheumatologists will see more patients where this mechanism of action is a concern. Lastly, radiation therapy may trigger severe skin thickening in patients with preexisting SSc or newly developed localized scleroderma .

A subset of patients may have cancer-induced autoimmunity with the diagnosis of cancer shortly preceding or following the first signs of the rheumatic illness . The two best examples of this are dermatomyositis and SSc (latter example discussed in detail subsequently). In both diseases, patients have (i) an increased risk of cancer, (ii) a striking temporal relationship between cancer diagnosis and rheumatic disease onset, (iii) particular autoantibody subsets that associate with cancer at the time of rheumatic disease onset (e.g., anti-RNA polymerase III in SSc and anti-NXP2 and anti-TIF1 gamma in dermatomyositis), and (iv) an increased expression of disease-associated antigens in cancer tissues . In dermatomyositis, the course of the disease also parallels the course of the cancer, with remission of dermatomyositis following an effective cancer therapy and relapse of dermatomyositis heralding cancer relapse. Case reports of patients with concurrent cancer and SSc also suggest that cancer therapy may be an effective antirheumatic disease therapy .

In addition to these possibilities, patients may have a shared genetic susceptibility to develop both cancer and autoimmune disease, or a common inciting exposure could trigger both diseases . Further studies are required to define the role of genetics and environmental exposures in the association between cancer and autoimmunity.

Recent investigations have provided compelling evidence that the link between cancer and autoimmune rheumatic diseases may indeed be bidirectional in nature. Here, we review more detailed data on two of these potential mechanisms, development of inflammation-induced cancer and cancer-induced autoimmunity, through the lens of SLE and SSc.

Mechanisms that may explain the increased risk of cancer in the autoimmune rheumatic diseases

An increased risk of cancer has been demonstrated across the broad spectrum of autoimmune rheumatic diseases. While it is beyond the scope of this article to review cancer risk in detail for all of the rheumatic diseases, Table 1 describes the magnitude of risk and specific tumor sites of concern based on the recently published meta-analyses for select diseases. A wide array of cancer types is observed, with an increased risk of both solid organ and hematologic malignancies.

The relationship between cancer and the autoimmune rheumatic diseases is complex with many potential mechanisms linking the two disease states ( Table 2 ). Malignancy may develop secondary to the rheumatic disease and its therapies. For instance, it has been proposed that chronic inflammation and tissue damage may stimulate cytokines and chemokines that further the development of malignancies through multiple mechanisms, including inducing DNA damage, inactivating tumor suppressor genes, stimulating enhanced cellular growth and survival, triggering angiogenesis, and enhancing invasion . Within the rheumatic diseases, a model of inflammation-induced cancer may be particularly important in systemic lupus erythematosus (SLE; detailed later), but other data also suggest the relevance of this mechanism in Sjogren’s syndrome, rheumatoid arthritis (RA), and systemic sclerosis (SSc). In Sjogren’s syndrome, studies have demonstrated that salivary gland enlargement, hypocomplementemia, neutropenia, cryoglobulinemia, splenomegaly, lymphadenopathy, longer disease duration, and lymphoid organization in labial salivary gland biopsies at diagnosis are predictive of lymphoma risk . In RA, an increased risk of cancer and greater cancer mortality have been observed in patients who have elevated inflammatory markers . In addition, a case–control study examining RA patients with lymphoma compared to RA controls suggested that long-term corticosteroid therapy, and administration of intra-articular steroids used to treat acute flares, were associated with a lower risk of lymphoma . In SSc, multiple studies have demonstrated an increased risk of lung cancer in patients with interstitial lung disease, although this has not been found consistently across all studies . However, data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, which enrolled >65,000 individuals, have demonstrated that baseline pulmonary scar is associated with future ipsilateral lung cancer, suggesting that this mechanism may also apply for patients with SSc .

Table 2

Potential mechanisms linking cancer and the autoimmune rheumatic diseases.

Proposed mechanism	Example(s)
Cancer secondary to rheumatic disease
Chronic inflammation and damage from rheumatic disease	1. Sjogren’s: disease activity, severity, and duration predictive of non-Hodgkin’s lymphoma risk 2. RA: elevated ESR and CRP associated with increased cancer risk; long-term corticosteroid therapy associated with lower lymphoma risk 3. SSc: pulmonary scar associated with lung cancer
Cytotoxic or biologic therapies	1. Cyclophosphamide: higher cumulative doses associated with an increased risk of lymphoproliferative and bladder cancers 2. Mycophenolate: Possible increase in nonmelanoma skin cancer and CNS lymphoma 3. TNF inhibitors: an increased risk of nonmelanoma and possibly melanoma skin cancer
Inability to clear oncogenic infections	SLE: risk higher for virus-associated cancers (e.g., cervical, vaginal/vulvar, and anal cancers associated with HPV)
Rheumatic disease secondary to cancer
Cancer-induced autoimmunity	1. SSc: an increased risk of cancer at disease onset among patients with RNA polymerase III autoantibodies; genetic abnormalities of POLR3A in cancers associated with mutation-specific T cell immune responses and cross-reactive autoantibodies 2. Dermatomyositis: striking clustering of cancer diagnosis with disease onset; an increased risk of CAM in patients with unique autoantibodies (NXP-2 and TIF-1 gamma); clinical improvement in DM with cancer therapy
Immunotherapy or chemotherapy	1. IL-2 therapy or immune checkpoint inhibitors: inflammatory arthritis and other autoimmune phenomena have been reported 2. Bleomycin and gemcitabine: associated with skin sclerosis, development of exacerbation of Raynaud’s and ischemic digits
Radiation therapy	Localized scleroderma may develop in radiation port
Shared etiology
Common inciting exposure	Silica, solvents, organic chemicals, pesticides, smoking, infections, and hormonal state
Shared genetic susceptibility	Increased risks of Hodgkin’s lymphoma in patients with a personal or family history of multiple autoimmune conditions

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