Patients with Breast Cancer The Effect of Antiestrogen Agents on Risk of Autoimmune Disorders in

Objective. To investigate the relationship between antiestrogen therapy in women with breast cancer and risk of autoimmune disease. Methods.We used a national database to assess the incidence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) following treatment with selective estrogen receptor modulators (SERM) or aromatase inhibitors (AI) in women with breast cancer. The total number of patients in our study was 190,620. Results. We observed highly significant, cumulative dose-dependent increased OR of incidence of both SLE and RA following treatment with SERM (p < 0.0001). The odds of developing RA were also increased following AI therapy (p < 0.001), but there was a trend for reduced odds of SLE, though this trend did not attain statistical significance (p = 0.070 for 2–11 months of treatment and p = 0.254 for 12+ months of treatment). Conclusion. Antiestrogen agents may have an important effect on risk of autoimmune disease. (First Release Oct 1 2014; J Rheumatol 2015;42:55–9; doi:10.3899/jrheum.140367) Key Indexing Terms: AUTOIMMUNE DISEASES SELECTIVE ESTROGEN RECEPTOR MODULATORS AROMATASE INHIBITORS ESTROGEN RECEPTOR-POSITIVE SYSTEMIC LUPUS ERYTHEMATOSUS RHEUMATOID ARTHRITIS From the Division of Rheumatology, Department of Medicine, MetroHealth Medical Center, Cleveland, Ohio, USA. J.Y. Chen, AB, Case Western Reserve University School of Medicine; S.P. Ballou, MD, Division of Rheumatology, Department of Medicine, MetroHealth Medical Center. Address correspondence to Dr. S.P. Ballou, Division of Rheumatology, MetroHealth Medical Center, 2500 Metrohealth Drive, Cleveland, Ohio 44109, USA. E-mail: [email protected] Accepted for publication August 26, 2014. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) can lead to severe morbidity and increased mortality, as well as drastically altered quality of life1,2. Women are 7 to 9 times more likely than men to develop SLE, while the female:male sex ratio is 2–3:1 for RA3. Estrogen may play a key role in these sex differences by influencing the immune response4, and numerous reports have established the importance of estrogen in induction of autoantibodies and promotion of disease activity in SLE3. Estrogen is produced from androgenic precursors through the enzymatic activity of aromatase and exerts its myriad effects by binding to receptors present on many tissues throughout the body. Both variations in estrogen receptor (ER) type5,6 and aromatase activity7,8 have been implicated in the mechanism of autoimmune disease. Thus, these elements have become the object of studies aimed at decreasing the expression and severity of autoimmune disorders. Drugs that target these factors, including selective ER modulators (SERM) such as tamoxifen, and aromatase inhibitors (AI) such as anastrazole, have long been available for treatment of ER–positive patients with breast cancer9. The purpose of our study was to investigate any relationship between the use of these therapies and the incidence of RA and SLE. Current data on the use of AI and SERM in patients with autoimmune disorders are equivocal or lacking in humans. A few studies exist on the effects of SERM on RA10 or SLE11, but they show no conclusive results. The effect of AI on these disorders has not been studied, to our knowledge. Further, the potential relationship between AI and SERM use and subsequent incidence of autoimmune disorders has not been studied. Our study explores the relationship between the use of SERM and AI and the subsequent diagnosis of SLE and RA using a retrospective cohort study of a large, de-identified patient database (Explore; Explorys Inc.)12. MATERIALS AND METHODS De-identified patient data were collected from a database containing records from patients seen in multiple healthcare systems across the United States from 1999 to 2013 (Explore; Explorys Inc.). The database standardizes patient data by mapping diagnoses into the Systematized Nomenclature for Medicine – Clinical Terms (SNOMED-CT). Drug prescriptions were categorized by class with SNOMED or by individual drug with RxNorm12. This database permits searching by demographics, diagnosis, and medicines prescribed, and months of treatment. Explorys searches result in output in terms of numbers of patients but do not yield average baseline statistics for cohorts such as age. The overall patient cohort was composed of all women over the age of 18 years who did not have a diagnosis of SLE or RA at the time of the breast cancer diagnosis. Among these patients, our control cohort comprised those who did not receive any SERM or AI treatment, and our experimental cohorts comprised those receiving 2–11 or 12+ months of Journal of Rheumatology The on January 30, 2015 Published by www.jrheum.org Downloaded from either SERM or AI. The OR of developing SLE or RA was set equal to 1.0 in the control group (patients without SERM or AI treatment). We chose to exclude patients who received only a single month of these agents (n = 3250 for the AI cohort and n = 2780 for the SERM cohort) to eliminate spurious results caused by isolated use. We also excluded the small number of patients who received both SERM and AI (n = 5340) because we found too few patients who went on to develop RA or SLE in this category to warrant appropriate statistical analysis. We chose to analyze the data at 12 months to review the effects of using the drug for a full year. Further categorization beyond this number (e.g., 18 or 24 mos) was precluded in this study owing to a lack of sufficient data. The incidence of autoimmune disorders was defined as the number of patients who received a diagnosis of SLE or RA at any time after cancer diagnosis for the control cohort and after initiating drug treatment for the experimental cohorts. For comparison, SLE and RA prevalence rates were calculated for the general female population over the age of 18, as well as the entire population of patients with breast cancer, regardless of drug treatment. For this study, the SERM chosen were tamoxifen, raloxifene, and toremifene; the AI were anastrazole, exemestane, formestane, letrozole, and aminoglutethimide. OR and logistic regression calculations were used to determine incidence rates and CI. Chi-squared analyses with a null hypothesis of p1 = p2 were performed to determine the statistical difference in disease incidence with various doses of AI or SERM therapy when compared to no treatment. These analyses were performed with R 3.0.2. Our study was approved by the Institutional Review Board of the MetroHealth Medical Center, Cleveland, Ohio, USA (approval number IRB13-00305). RESULTS Over 12 million patients fit our initial search criteria, with 238,880 diagnoses of breast cancer of any type. We studied the OR of incidence of SLE and RA in patients diagnosed with breast cancer who received antiestrogen agents, compared with our control cohort of 190,620 patients with breast cancer who did not receive antiestrogen therapy. Our results are shown in Table 1. Patients receiving any SERM had a cumulative dose-dependent increased OR of developing both RA [1.26 for 2-11 months (95% CI 1.13-1.41; p = 3.61 × 10-5); 2.41 for 12+ months (95% CI 1.92-3.02; p = 3.95 × 10-16)] and SLE [1.41 for 2–11 months (95% CI 1.16–1.71; p = 4.76 × 10-4); 2.02 for 12+ months (95% CI 1.29–3.15; p = 1.41 × 10-3)]. This relationship was also observed for the use of AI and the risk of developing RA [1.32 for 2-11 months (95% CI 1.21–1.44; p = 4.14 × 10-11); 1.85 for 12+ months (95% CI 1.57–2.17; p = 4.23 × 10-15)]. When taking into account Bonferroni’s correction for multiple comparisons, the p value for significance (with 4 group comparisons) between any 2 groups is p = 0.0125. The calculated p values show that even after this correction, the data are still highly statistically significant. In contrast, patients receiving any AI had a decreased OR of developing SLE (0.84 for 2–11 months; 0.77 for 12+ months); however, these results were not statistically significant (95% CI 0.70–1.02; p = 0.070; and 95% CI 0.50–1.21; p = 0.254, respectively). Because of the recent availability of the database used for this study, we intended to validate our approach. We used the database to assess the prevalence of SLE and RA in the general population (all females over the age of 18) as well as in all patients with breast cancer, regardless of treatment received (Table 2). The prevalence rates we observed for the general female population were consistent with those reported in large epidemiological studies1,2. Further, the database estimate of breast cancer prevalence in females, 2.0%, roughly corresponds with the value derived from literature, 1.8%13. DISCUSSION We found a cumulative, dose-dependent, positive correlation between the use of SERM and subsequent diagnoses of RA and SLE, as shown in Figures 1 and 2. Given the statistical significance of this association and the temporal precedence of treatment prior to disease diagnosis of RA or SLE, our findings suggest a possible causative influence of these drugs on the incidence of these autoimmune diseases. It is possible that some type of selection bias related to more extensive diagnostic testing in women with breast cancer (including possibly rheumatoid factor and antinuclear antibody tests) than in “healthy women” could influence the diagnosis of these autoimmune disorders. Such a possibility might partly explain the slightly increased prevalence of SLE and RA among all patients with breast cancer, compared with healthy women (Table 2). However, we would not expect such a situation to apply between patients with breast cancer who did and those who did not receive antiestrogen therapy (our control cohort). With regard to use of AI, we also observed a statistically significant cumulative dose-dependent increased OR of RA (Figure 1). This finding 56 The Journal of Rheumatology 2015; 42:1; doi:10.3899/jrheum.140367 Personal non-commercial use only. The Journal of Rheumatology Copyright © 2015. All rights reserved. Table 1. Antiestrogen use and incidence of RA and SLE in patients with breast cancer. RA SLE Drug Mos of Treatment Total Patients N Rate, % OR (95% CI) N Rate, % OR (95% CI) None 0 190,620 4460 2.34 1.00 (ref) 1330 0.70 1.00 (ref) SERM 2–11 11,180 330 2.95 1.26*** (1.13–1.41) 110 0.98 1.41*** (1.16–1.71) 12+ 1420 80 5.63 2.41*** (1.92–3.02) 20 1.41 2.02** (1.29–3.15) AI 2–11 20,420 630 3.09 1.32*** (1.21–1.44) 120 0.59 0.84 (0.70–1.02) 12+ 3700 160 4.32 1.85*** (1.57–2.17) 20 0.54 0.77 (0.50–1.21) Statistically significant at ** p < 0.01, *** p < 0.001. SERM: selective estrogen receptor modulator; AI: aromatase inhibitor; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus. Journal of Rheumatology The on January 30, 2015 Published by www.jrheum.org Downloaded from 57 Chen and Ballou: Antiestrogens and autoimmune disorders Personal non-commercial use only. The Journal of Rheumatology Copyright © 2015. All rights reserved. Table 2. SLE and RA prevalence in women 18+ years and all patients with breast cancer. Cohort Patients Patients SLE Patients RA in Cohort with SLE Prevalence with RA Prevalence All women 18+ yrs 12,087,760 46,590 0.39% 117,580 0.97% Patients with breast cancer 238,88