Although the female predominance of autoimmune diseases is not completely understood, sex hormones are thought to play a role. Attention to lifelong reproductive health is especially important for women with autoimmune disorders. Many of these women require long-term immunosuppressive therapy that may affect their ability to clear infections, including viruses, and may alter natural tumor surveillance mechanisms. As a result, women with autoimmune diseases may have different risks for common reproductive-related malignancies that may in turn affect screening guidelines and other preventive measures, including vaccination. Women with autoimmune diseases need to adhere diligently to screening recommendations.
Key points
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Advances in treatment of autoimmune diseases have led to a reduction in mortality and increased quality of life for these patients, making issues related to long-term preventive health and aging more relevant.
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Immune dysregulation from immunosuppressant medications or the underlying diseases may affect clearance of viral infections or innate tumor surveillance among people with autoimmune diseases.
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Breast cancer risk does not seem to be increased among women with rheumatoid arthritis or systemic lupus erythematosus compared with the general female population.
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Studies are conflicting regarding the relative risk of invasive cervical cancer in women with autoimmune diseases, but there is concern for increased rates of precancerous lesions, including cervical dysplasia and atypia, for which early treatment may affect the development of invasive cancer.
Introduction
It is well known that many systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), carry a striking female predominance. Reasons for this are thought to be multifactorial, but likely involve interrelationships between female sex hormones and the immune system. Because of this correlation, there is concern about the influence of autoimmune disease on the reproductive health of affected women. Aside from well-studied influences of underlying disease on pregnancy, there remains concern that common triggering factors may influence the development of both autoimmune disease and hormonal malignancies. There is additional concern that the presence of autoimmunity or chronic immunosuppressive medication may mediate risk of chronic viral infections, including human papilloma virus (HPV), known to cause cervical and other malignancies.
Required reporting of invasive cancers to national cancer registries has allowed the estimation of site-specific malignancies by age, race, and gender in the general population. By studying rates observed in large cohorts of autoimmune diseases, standardized incidence ratios (SIRs; the ratio of observed cancers to those expected based on age and gender norms) can be calculated to study the rates of cancer, including female malignancies, providing an easy reference of relative risk of these malignancies that may influence screening practices. This method has been widely used to study the changes in risk of hematologic malignancies and lymphoma in patients with RA who use tumor necrosis factor (TNF) inhibitor medications.
Given increased survival rates and improved disease management for many patients with RA and SLE, attention to the risks and development of comorbid conditions, including cancer, has become more important for patients and their providers. Relative risks of hormone-based malignancies, as well as the identification of specific disease-related or medication-related risks, are critical when caring for women with autoimmune disease across their lifespan so that appropriate screening and preventive services can be implemented as part of comprehensive health care. Admittedly, many patients with underlying systemic autoimmune diseases see their rheumatologists for management of active disease manifestations, and minimization of medication toxicities and/or visits to primary care or other preventive health services may become less prioritized. It is important to understand the rates of breast and cervical cancers in women with SLE and RA, risk factors for development of malignancies, and appropriate screening procedures. The addition of a primary care provider to the medical team may greatly enhance adherence to preventive screening for cancer as well as other comorbid conditions that could complicate underlying autoimmune disease.
Introduction
It is well known that many systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), carry a striking female predominance. Reasons for this are thought to be multifactorial, but likely involve interrelationships between female sex hormones and the immune system. Because of this correlation, there is concern about the influence of autoimmune disease on the reproductive health of affected women. Aside from well-studied influences of underlying disease on pregnancy, there remains concern that common triggering factors may influence the development of both autoimmune disease and hormonal malignancies. There is additional concern that the presence of autoimmunity or chronic immunosuppressive medication may mediate risk of chronic viral infections, including human papilloma virus (HPV), known to cause cervical and other malignancies.
Required reporting of invasive cancers to national cancer registries has allowed the estimation of site-specific malignancies by age, race, and gender in the general population. By studying rates observed in large cohorts of autoimmune diseases, standardized incidence ratios (SIRs; the ratio of observed cancers to those expected based on age and gender norms) can be calculated to study the rates of cancer, including female malignancies, providing an easy reference of relative risk of these malignancies that may influence screening practices. This method has been widely used to study the changes in risk of hematologic malignancies and lymphoma in patients with RA who use tumor necrosis factor (TNF) inhibitor medications.
Given increased survival rates and improved disease management for many patients with RA and SLE, attention to the risks and development of comorbid conditions, including cancer, has become more important for patients and their providers. Relative risks of hormone-based malignancies, as well as the identification of specific disease-related or medication-related risks, are critical when caring for women with autoimmune disease across their lifespan so that appropriate screening and preventive services can be implemented as part of comprehensive health care. Admittedly, many patients with underlying systemic autoimmune diseases see their rheumatologists for management of active disease manifestations, and minimization of medication toxicities and/or visits to primary care or other preventive health services may become less prioritized. It is important to understand the rates of breast and cervical cancers in women with SLE and RA, risk factors for development of malignancies, and appropriate screening procedures. The addition of a primary care provider to the medical team may greatly enhance adherence to preventive screening for cancer as well as other comorbid conditions that could complicate underlying autoimmune disease.
Breast cancer
Breast cancer is the most common malignancy seen in the general female population, with approximately 1.7 million cases diagnosed worldwide in 2012. Known risk factors for the development of breast cancer include family history, age, race, parity, breastfeeding, use of exogenous estrogens, alcohol, sedentary lifestyle, and increased body mass index. Given that autoimmune diseases often preferentially affect women and may bear unique relationships with female sex hormones, it is important to understand the relative risk of breast cancer among women affected by these chronic diseases. Several large multinational studies have been performed to compare rates of numerous types of cancers in patients with autoimmune diseases and the general population. For example, it is well known that many autoimmune diseases increase the risk of lymphoma compared with the general population, although the absolute risk remains low.
Breast Cancer and Systemic Lupus Erythematosus
Several large studies and meta-analyses have been published to examine the SIR of breast cancer in women with SLE. One of the largest studies was performed by the international Systemic Lupus International Collaborating Clinics (SLICC), in which 16,000 patients with SLE from 30 participating centers were followed longitudinally. A total of 180 cases of breast cancer were reported: the average age at diagnosis was 54 years, which is younger than the mean of 60 years in the general population, with a mean SLE duration of 14 years. The SIR of overall breast cancer in this SLE population was 0.73 (95% confidence interval [CI], 0.61–0.88), indicating a lower than expected incidence of breast cancer in SLE. A separate group performed an analysis of breast cancer incidence among women with or without SLE enrolled in a population-based study of US Medicare recipients. A cohort of 18,423 women with a diagnosis of SLE was compared with 3,651,715 women without SLE. The 5-year age-adjusted incidence risk for patients with SLE overall was 2.23 (95% CI, 1.94–2.55) per 100 women compared with 2.59 (95% CI, 2.57–2.61) among women without SLE, with an overall unadjusted risk ratio of 0.87 (95% CI, 0.79–0.86), confirming the SLICC results showing no increased risk of breast cancer. These results were similar when examining breast cancer risk in subgroups of women by race or age (older or younger than 65 years). Furthermore, a separate study of the United States Renal Data System evaluated site-specific cancer risk in renal transplant recipients, comparing rates of cancer in 4289 transplant recipients with SLE versus 139,363 transplant recipients without SLE with what would be expected in the general population. The overall SIR for cancer was increased for all transplant recipients by approximately 3-fold: 3.5 (95% CI, 2.1–5.7) for SLE and 3.7 (95% CI, 2.4–5.7) for non-SLE. Similarly, breast cancer showed an increased incidence in all transplant recipients by approximately 2-fold, but this was not different between patients with and without SLE, suggesting that the increased risk of breast cancer may be related more to end-stage renal disease, dialysis, and transplantation rather than SLE-specific factors.
In order to better understand demographic and disease-related risk factors for breast cancer among women with SLE, the SLICC group performed a case-cohort analyses of a subset of the patients with SLE who developed breast cancer compared with cancer-free patients with SLE. Eighty-six women with SLE diagnosed with breast cancer were compared with 4498 cancer-free women with SLE. Women with breast cancer were older than the cancer-free controls and more likely to be white (81% vs 62%). There were no significant differences in disease activity over time or autoantibody prevalence between the groups. In univariate analyses, only age, white ancestry, menopausal status, postmenopausal hormone therapy, and family history of breast cancer were associated with breast cancer risk, which is similar to what is seen in the general population. However, in multivariable analysis, only increasing age remained statistically significant. Variables related to SLE disease activity, autoantibody prevalence, or medication use were not associated with breast cancer risk in this international cohort. Thus, although some data suggest a possible decreased risk of breast cancer among patients with SLE, other data suggest it is similar. To date, no disease-related factors seem to mitigate breast cancer risk in women with SLE. Male breast cancer in SLE has not been systematically studied.
Rheumatoid Arthritis and Breast Cancer
Similar to SLE, overall malignancy rates for RA seem to be slightly increased compared with the general population, with most of the increases seen in the hematologic malignancies. Also like SLE, rates of breast cancer among women with RA seem to be lower than what is expected based on age and ethnicity. The introduction and widespread use of biologic therapies for RA have changed clinical practice since the turn of the century. Given the addition of biologic therapies and the possibility of affecting rates of malignancies seen in patients with RA, a recent meta-analysis was performed evaluating studies published from 2008 to 2014. The pooled SIR for breast cancer in this meta-analysis of 0.84 (95% CI, 0.73–1.01) was similar to the pooled SIR found in an earlier meta-analysis (pre–biologic therapy use) of 0.83 (95% CI, 0.79–0.90), the main change being that the CI now crosses the null. Therefore, the conclusion that breast cancer risk does not seem to be increased in women with RA is upheld even with the addition of different RA treatment strategies, although the decrease in rate is no longer consistent. A separate meta-analysis, isolated to breast cancer in RA, was performed that showed consistent results of a numerically decreased rate of breast cancer compared with the general population. However, this study went further to evaluate breast cancer risk by ethnicity, identifying an increased risk for breast cancer among nonwhite women with RA compared with the general population. The slightly reduced risk of breast cancer among white women with RA was similar to that seen in the overall RA population.
Given the concern about reduced tumor surveillance with the use of TNF antagonists, there has been hesitancy for initiating these agents in patients with RA with a remote history of breast cancer. Two studies have been recently been published to evaluate the change in risk to women with RA with a history of breast cancer who begin therapy with TNF antagonists. The first study evaluated a cohort of 143 Swedish patients with RA with a history of breast cancer who were later initiated on TNF antagonist therapy and compared them with 143 (out of a total of 1598) patients with RA with a history of breast cancer who were not treated with biologic therapy. Subjects were matched on sex, age at cancer diagnosis, year of cancer diagnosis, and stage of cancer at diagnosis, and were followed for approximately 5 years for breast cancer recurrence. Patients who started TNF therapy did so after approximately 9 years from original cancer diagnosis, generally following previous guidelines to wait at least 5 years before initiating biologic therapy. The study did not find an increased risk of breast cancer recurrence between groups, with a hazard ratio of 0.8 (95% CI, 0.3–2.1), although the sample size was small. These data were supported by a larger study of breast cancer recurrence in a Medicare population including women with RA or inflammatory bowel disease. The larger population (a total of 2684 women) under study allowed for an analysis not only of the effects of TNF inhibition on cancer recurrence but also of other commonly used immunosuppressive medications, including methotrexate and thiopurines. Women with each exposure were matched to a cohort of women without the medication exposure and were analyzed separately. Numerically, the hazard ratio was increased for users of all 3 therapies compared with nonusers, but the CIs were wide and crossed the null, therefore not establishing a statistically significant increase. Many of these women initiated immunosuppressive therapy for autoimmune disease before or shortly following initial diagnosis of breast cancer. Thus, a history of breast cancer should not necessarily preclude the use of traditional disease-modifying antirheumatic drugs (DMARDs) or biologic therapies for management of active RA.
Recommendations for Screening for Breast Cancer
Despite some data suggesting a possible decreased incidence of breast cancer in women with RA compared with the general population, women with RA should not think themselves protected from developing one of the most common cancers among women worldwide, nor should they develop a sense of complacency regarding routine health screening for breast cancer. The main risk factors for breast cancer for women with RA are not different from those of women without RA: increasing age, family history, menopausal status, and use of postmenopausal hormone therapy are among the most important risk factors. Women with RA should follow the same screening recommendations as women without RA regarding breast cancer, based on the presence and number of risk factors. Similar to the general population, any palpable, visual, or radiographic changes to the breast that raise suspicion for breast cancer should prompt a thorough evaluation.
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