An autoimmune disease (AD) occurs when the body’s immune system mistakenly attacks its own healthy cells and tissues. Cancer involves the uncontrolled growth and division of abnormal cells. While having an AD does not directly cause cancer, the two conditions are linked by a complex association that results in an elevated risk for developing certain malignancies. This increased risk is a consequence of shared biological pathways and, in some cases, the treatments used to manage the autoimmune condition.
Understanding the Association, Not Direct Causation
An autoimmune disease is generally an associated risk factor, not a direct cause of cancer. Epidemiological studies consistently show a correlation, indicating that populations with ADs develop certain cancers at a higher rate than the general population. This relationship is not a simple cause-and-effect but rather a shared susceptibility involving similar genetic factors and immune system irregularities.
This increased likelihood is often described using the concept of relative risk (RR), which compares the probability of an event in an exposed group to an unexposed group. A relative risk greater than 1.0 means the exposed group, such as those with an AD, has a higher risk for a specific cancer. For example, an RR of 2.0 indicates a person with the AD is two times more likely to develop that cancer compared to someone without it. However, a high relative risk can still translate to a small absolute increase in an individual’s lifetime chance of developing the malignancy.
Biological Pathways Linking Autoimmunity and Malignancy
The connection between AD and malignancy is rooted in two distinct biological mechanisms arising from a dysregulated immune system. The first involves creating an environment that promotes tumor growth, while the second relates to the failure of the body’s defense system to eliminate abnormal cells.
Chronic Inflammation
Chronic inflammation, the hallmark of many autoimmune diseases, creates a microenvironment highly conducive to DNA damage and cellular transformation. The immune cells deployed during long-term inflammation, such as phagocytes, produce a persistent stream of reactive oxygen and nitrogen species (RONS). While these RONS are intended to neutralize perceived threats, they also act as collateral damage, chemically modifying DNA bases in healthy, surrounding tissue.
This oxidative stress can lead to mutations, such as the formation of 5-chlorocytosine (5ClC), which accumulates over time and promotes genomic instability. Furthermore, the continuous cycle of tissue damage and cellular proliferation required for repair synergistically increases the rate at which these mutations occur. Cells with accumulated DNA damage are more likely to escape normal regulatory mechanisms and begin the uncontrolled growth characteristic of malignancy.
Compromised Immune Surveillance
The second mechanism relates to the failure of immune surveillance, which is the body’s natural process of identifying and destroying newly formed cancer cells. In many autoimmune conditions, the immune system is dysfunctional and misdirected, focused on attacking self-tissue rather than monitoring for genuine threats. This chronic state of immune dysregulation impairs the ability of T-cells and other immune components to recognize and eliminate malignant cells.
This failure allows nascent tumors to evade detection and proliferate unchecked, a process known as immune escape. In some ADs, chronic overstimulation and proliferation of B-cells can eventually lead to the malignant transformation of those very immune cells. The resulting lymphoma is a direct consequence of the sustained, abnormal immune activity characteristic of the disease.
Specific Autoimmune Diseases with Elevated Cancer Risk
Inflammatory Bowel Disease (IBD)
Inflammatory Bowel Disease (IBD), which includes Crohn’s disease and Ulcerative Colitis, is linked to a substantially increased risk of colorectal cancer (CRC). This risk is a classic example of the chronic inflammation pathway, where long-standing mucosal inflammation leads to a specific tumor progression sequence. Patients with extensive colonic involvement have a relative risk for CRC that can be approximately 4.5 times higher than the general population, with a cumulative risk that increases with disease duration.
Sjögren’s Syndrome
Sjögren’s Syndrome carries one of the highest relative risks for developing Non-Hodgkin’s Lymphoma (NHL) among all autoimmune diseases. The risk is estimated to be between six and nine times greater than the general population. This malignancy primarily arises from chronic B-cell overactivity, where the sustained, abnormal stimulation of B-lymphocytes drives the eventual malignant transformation. The most common resulting cancer is a slow-growing type called mucosa-associated lymphoid tissue (MALT) lymphoma.
Systemic Lupus Erythematosus (SLE)
Systemic Lupus Erythematosus (SLE) is associated with an elevated risk for certain hematological cancers, particularly NHL, due to the underlying immune dysregulation and B-cell hyperactivity. Women with SLE also show an increased incidence of cervical dysplasia, which is a pre-cancerous condition of the cervix. This heightened risk is thought to be mediated by the body’s impaired ability to clear the Human Papilloma Virus (HPV), which is the primary cause of cervical cancer.
Rheumatoid Arthritis (RA)
Rheumatoid Arthritis (RA) is associated with an increased risk of lung cancer, even when accounting for shared risk factors like smoking. The augmented risk is estimated to be over 50% higher than the general population. This is primarily attributed to the chronic inflammatory state of RA, particularly in the lungs. Patients with RA-associated interstitial lung disease (RA-ILD) face a risk that can be up to three times higher.
Treatment-Related Cancer Risk Factors
The medications used to control autoimmune disease activity can introduce a separate, independent set of cancer risk factors. These necessary treatments, which include immunosuppressive and immunomodulatory drugs, work by broadly suppressing the immune system to halt the attack on self-tissue. By suppressing the immune system, however, they can reduce the body’s ability to find and destroy abnormal cells before they become tumors.
The use of conventional immunosuppressants like azathioprine, methotrexate, and cyclophosphamide has been linked to a dose-dependent and cumulative risk of certain malignancies. Cyclophosphamide, in particular, is associated with an increased risk of bladder cancer and certain leukemias. Additionally, prolonged immune suppression can raise the risk for non-melanoma skin cancers and lymphomas, as the immune system is less able to control viral infections or clear pre-cancerous cells. Physicians manage this by performing a careful risk-benefit analysis, as the severe progression of the autoimmune disease itself can pose a greater threat than the medication’s risk of malignancy.