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Vol. 184, No. 1 DOI: 10.1093/aje/kwv307 Advance Access publication: June 6, 2016
Original Contribution Androgen Deprivation Therapy and the Incidence of Inflammatory Bowel Disease in Patients With Prostate Cancer
Adi J. Klil-Drori, Koray Tascilar, Hui Yin, Armen Aprikian, Alain Bitton, and Laurent Azoulay* * Correspondence to Dr. Laurent Azoulay, Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine, H-425.1, Montreal, QC H3T 1E2, Canada (e-mail: [email protected]).
Initially submitted September 3, 2015; accepted for publication November 3, 2015.
Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. By lowering androgen levels, ADT inhibits the progression of prostate cancer, but it may also affect gut autoimmunity. We investigated the association between ADT and the incidence of inflammatory bowel disease using a cohort of 31,842 men newly diagnosed with prostate cancer between 1988 and 2014, identified in the United Kingdom Clinical Practice Research Datalink. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays, with nonuse as the reference category. During 133,018 person-years of follow-up, 48 men were newly diagnosed with ulcerative colitis (incidence rate (IR) = 36/100,000 person-years (PY)) and 12 were diagnosed with Crohn’s disease (IR = 9/100,000 PY). In Cox proportional hazards models, ADT was associated with a decreased risk of ulcerative colitis (IR = 24/100,000 PY vs. IR = 50/100,000 PY; hazard ratio = 0.52, 95% confidence interval: 0.28, 0.99) and a nonsignificant decreased risk of Crohn’s disease (hazard ratio = 0.38, 95% confidence interval: 0.11, 1.37). These findings indicate that the use of ADT may be associated with intestinal autoimmunity. Further research is warranted to replicate these findings and assess their clinical significance. androgen deprivation therapy; androgens; Crohn’s disease; prostate cancer; ulcerative colitis
Abbreviations: ADT, androgen deprivation therapy; BMI, body mass index; CD, Crohn’s disease; CI, confidence interval; CPRD, Clinical Practice Research Datalink; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; IBD, inflammatory bowel disease; UC, ulcerative colitis.
not subject to sex bias (10), may also be influenced by the use of exogenous hormones, such as oral contraceptives and hormone replacement therapy (11, 12). This may point to a complex interplay between sex hormones, the immune system, changes in the mucosal barrier (13, 14), and the intestinal microbiome (15) that propel intestinal inflammation. In line with this hypothesis, androgen deprivation through surgical castration has been shown to protect against increased intestinal permeability in a porcine model of gut injury (16), while surgical castration and antiandrogens have been shown to affect the composition of murine gut microbiota (17, 18). Thus, through these mechanisms, it is biologically plausible that ADT may affect the onset of IBD. To date, the association between androgen deprivation and the incidence of adult IBD has not been investigated. Thus, our objective in this population-based study was to determine
Since the seminal work by Huggins and Hodges in 1941 (1), the hypogonadism induced by androgen deprivation therapy (ADT) has been shown to improve outcomes in patients with prostate cancer, and has thus become the mainstay treatment for patients with advanced disease (2, 3). While it is well established that androgens play a role in prostate cancer development, these hormones may also regulate certain aspects of human immunity (4). It is thus compelling that current knowledge on the immune effects of the persistent androgen deprivation achieved by ADT remains limited (5, 6). The hypothesis that sex hormones, such as androgens and estrogens, may play a role in the pathogenesis of autoimmunity is based on the sex bias of several autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and glomerular basement membrane disease (7–9). There is now evidence that inflammatory bowel disease (IBD), a disease 15
Am J Epidemiol. 2016;184(1):15–22
16 Klil-Drori et al.
whether the use of ADT is associated with the incidence of IBD in men with prostate cancer. METHODS Data source
This study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD is the world’s largest primary-care database, containing information on more than 13 million individuals across 680 general practices. The CPRD contains data on demographic characteristics, clinical diagnoses, and prescriptions written by general practitioners. Patients in the CPRD have been shown to be representative of the United Kingdom population in terms of age, sex, ethnicity, and body mass index (BMI) (19). Diagnoses recorded in the CPRD have been shown to have excellent validity, with a median positive predictive value of 88.6% for all diagnoses (20). The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD ( protocol number 14_228) and the Research Ethics Committee of the Jewish General Hospital (Montreal, Quebec, Canada). Study population
Using the CPRD, we identified a cohort of men aged ≥40 years newly diagnosed with prostate cancer between January 1, 1988, and September 30, 2013. Cohort entry was defined by the date of the prostate cancer diagnosis. Patients with less than 1 year of registration with an up-to-standard general medical practice prior to cohort entry were excluded, as were those previously diagnosed with IBD (using a broad range of specific and nonspecific codes (e.g., chronic enteritis)), ischemic colitis, or diverticulitis at any time before cohort entry. Ischemic colitis and diverticulitis are the main differential diagnoses of elderly-onset IBD (21) and were therefore considered both exclusion and censoring criteria. Further, patients with ADT prescriptions prior to cohort entry (suggesting prevalent prostate cancer) were excluded. Lastly, we excluded all patients with less than 1 year of follow-up, as events occurring in the first year may have indicated prevalent cases given the known diagnostic delays associated with IBD (22). Patients meeting the study inclusion criteria were followed until an incident diagnosis of IBD (defined below) or were censored upon an incident diagnosis of ischemic colitis or diverticulitis, death from any cause, end of registration with the general practice, or the end of the study period (September 30, 2014), whichever occurred first.
(21), patients were considered exposed starting 1 year after the date of the first ADT prescription or the date of bilateral orchiectomy (i.e., after applying a 1-year lag) and continuing until the end of follow-up. The use of a 1-year lag period was done for latency purposes (i.e., to impose a minimum amount of time between exposure and event) and to minimize misclassification associated with diagnostic delays for IBD (22). Nonuse of ADT served as the reference category for all analyses. Definition of IBD
We identified all incident diagnoses of ulcerative colitis (UC) and Crohn’s disease (CD) during follow-up on the basis of Read codes (23), which are provided in Web Table 1 (available at http://aje.oxfordjournals.org/). Overall, IBD has been shown to be well recorded in the CPRD. Diagnostic codes for UC and CD were both shown to have a positive predictive value of 92% among patients with prevalent disease (24). In another validation study, 92% of the IBD codes were supported by gastroenterology consultations, surgery, endoscopy, barium studies, or intestinal biopsy (23). In addition, the time interval between the date of incident IBD diagnosis reported by the general practitioner participating in the survey and the date recorded in the CPRD was less than 30 days in two-thirds of the cases (23). Finally, 87% of the first-ever IBD diagnoses recorded in the CPRD have been shown to be incident cases (25). Statistical analysis
Descriptive statistics were used to summarize the characteristics of the cohort, overall as well as separately for patients exposed and unexposed to ADT in the first 6 months of follow-up. Crude incidence rates for all IBD, UC, and CD were estimated by dividing the total number of events by the total number of person-years of follow-up, with 95% confidence intervals based on a Poisson distribution. Cox proportional hazards models using a time-varying exposure definition were used to estimate hazard ratios and 95% confidence intervals for all IBD, UC, and CD associated with the use of ADT, when compared with nonuse. This was considered the primary analysis. All model results were adjusted for the following potential confounders, measured at cohort entry: age (years), calendar year of cohort entry, smoking status (categorized as former, current, or never smoker), BMI (weight (kg)/height (m)2), prostate-specific antigen level (ng/mL), and use of nonsteroidal antiinflammatory drugs in the year before cohort entry. Variables with missing information were coded as “unknown.” Secondary analyses
Exposure assessment
Exposure to ADT consisted of gonadotropin-releasing hormone (GnRH) agonists (leuprolide, buserelin, goserelin, triptorelin), oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide), estrogens (diethylstilbestrol, estramustine), and bilateral orchiectomy. A time-dependent exposure definition was used, which allowed patients to move from a period of nonexposure to a period of exposure. Given the persistent nature of the hypogonadism induced by ADT
We conducted 3 secondary analyses, all with nonuse of ADT as the reference category. First, we repeated the primary analysis to assess whether the incidence of all IBD, UC, and CD varied according to the use of specific types of ADT. Thus, for this analysis, use of ADT was further classified into 2 groups: GnRH agonists (alone or in combination with other ADT types) and other ADTs. In the other two analyses, we assessed whether there was effect modification by BMI and smoking status by including in the models terms Am J Epidemiol. 2016;184(1):15–22
Androgen Deprivation Therapy and Inflammatory Bowel Disease 17
for interaction between exposure and these variables, categorized as BMI
Vol. 184, No. 1 DOI: 10.1093/aje/kwv307 Advance Access publication: June 6, 2016
Original Contribution Androgen Deprivation Therapy and the Incidence of Inflammatory Bowel Disease in Patients With Prostate Cancer
Adi J. Klil-Drori, Koray Tascilar, Hui Yin, Armen Aprikian, Alain Bitton, and Laurent Azoulay* * Correspondence to Dr. Laurent Azoulay, Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine, H-425.1, Montreal, QC H3T 1E2, Canada (e-mail: [email protected]).
Initially submitted September 3, 2015; accepted for publication November 3, 2015.
Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. By lowering androgen levels, ADT inhibits the progression of prostate cancer, but it may also affect gut autoimmunity. We investigated the association between ADT and the incidence of inflammatory bowel disease using a cohort of 31,842 men newly diagnosed with prostate cancer between 1988 and 2014, identified in the United Kingdom Clinical Practice Research Datalink. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays, with nonuse as the reference category. During 133,018 person-years of follow-up, 48 men were newly diagnosed with ulcerative colitis (incidence rate (IR) = 36/100,000 person-years (PY)) and 12 were diagnosed with Crohn’s disease (IR = 9/100,000 PY). In Cox proportional hazards models, ADT was associated with a decreased risk of ulcerative colitis (IR = 24/100,000 PY vs. IR = 50/100,000 PY; hazard ratio = 0.52, 95% confidence interval: 0.28, 0.99) and a nonsignificant decreased risk of Crohn’s disease (hazard ratio = 0.38, 95% confidence interval: 0.11, 1.37). These findings indicate that the use of ADT may be associated with intestinal autoimmunity. Further research is warranted to replicate these findings and assess their clinical significance. androgen deprivation therapy; androgens; Crohn’s disease; prostate cancer; ulcerative colitis
Abbreviations: ADT, androgen deprivation therapy; BMI, body mass index; CD, Crohn’s disease; CI, confidence interval; CPRD, Clinical Practice Research Datalink; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; IBD, inflammatory bowel disease; UC, ulcerative colitis.
not subject to sex bias (10), may also be influenced by the use of exogenous hormones, such as oral contraceptives and hormone replacement therapy (11, 12). This may point to a complex interplay between sex hormones, the immune system, changes in the mucosal barrier (13, 14), and the intestinal microbiome (15) that propel intestinal inflammation. In line with this hypothesis, androgen deprivation through surgical castration has been shown to protect against increased intestinal permeability in a porcine model of gut injury (16), while surgical castration and antiandrogens have been shown to affect the composition of murine gut microbiota (17, 18). Thus, through these mechanisms, it is biologically plausible that ADT may affect the onset of IBD. To date, the association between androgen deprivation and the incidence of adult IBD has not been investigated. Thus, our objective in this population-based study was to determine
Since the seminal work by Huggins and Hodges in 1941 (1), the hypogonadism induced by androgen deprivation therapy (ADT) has been shown to improve outcomes in patients with prostate cancer, and has thus become the mainstay treatment for patients with advanced disease (2, 3). While it is well established that androgens play a role in prostate cancer development, these hormones may also regulate certain aspects of human immunity (4). It is thus compelling that current knowledge on the immune effects of the persistent androgen deprivation achieved by ADT remains limited (5, 6). The hypothesis that sex hormones, such as androgens and estrogens, may play a role in the pathogenesis of autoimmunity is based on the sex bias of several autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and glomerular basement membrane disease (7–9). There is now evidence that inflammatory bowel disease (IBD), a disease 15
Am J Epidemiol. 2016;184(1):15–22
16 Klil-Drori et al.
whether the use of ADT is associated with the incidence of IBD in men with prostate cancer. METHODS Data source
This study was conducted using the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD is the world’s largest primary-care database, containing information on more than 13 million individuals across 680 general practices. The CPRD contains data on demographic characteristics, clinical diagnoses, and prescriptions written by general practitioners. Patients in the CPRD have been shown to be representative of the United Kingdom population in terms of age, sex, ethnicity, and body mass index (BMI) (19). Diagnoses recorded in the CPRD have been shown to have excellent validity, with a median positive predictive value of 88.6% for all diagnoses (20). The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD ( protocol number 14_228) and the Research Ethics Committee of the Jewish General Hospital (Montreal, Quebec, Canada). Study population
Using the CPRD, we identified a cohort of men aged ≥40 years newly diagnosed with prostate cancer between January 1, 1988, and September 30, 2013. Cohort entry was defined by the date of the prostate cancer diagnosis. Patients with less than 1 year of registration with an up-to-standard general medical practice prior to cohort entry were excluded, as were those previously diagnosed with IBD (using a broad range of specific and nonspecific codes (e.g., chronic enteritis)), ischemic colitis, or diverticulitis at any time before cohort entry. Ischemic colitis and diverticulitis are the main differential diagnoses of elderly-onset IBD (21) and were therefore considered both exclusion and censoring criteria. Further, patients with ADT prescriptions prior to cohort entry (suggesting prevalent prostate cancer) were excluded. Lastly, we excluded all patients with less than 1 year of follow-up, as events occurring in the first year may have indicated prevalent cases given the known diagnostic delays associated with IBD (22). Patients meeting the study inclusion criteria were followed until an incident diagnosis of IBD (defined below) or were censored upon an incident diagnosis of ischemic colitis or diverticulitis, death from any cause, end of registration with the general practice, or the end of the study period (September 30, 2014), whichever occurred first.
(21), patients were considered exposed starting 1 year after the date of the first ADT prescription or the date of bilateral orchiectomy (i.e., after applying a 1-year lag) and continuing until the end of follow-up. The use of a 1-year lag period was done for latency purposes (i.e., to impose a minimum amount of time between exposure and event) and to minimize misclassification associated with diagnostic delays for IBD (22). Nonuse of ADT served as the reference category for all analyses. Definition of IBD
We identified all incident diagnoses of ulcerative colitis (UC) and Crohn’s disease (CD) during follow-up on the basis of Read codes (23), which are provided in Web Table 1 (available at http://aje.oxfordjournals.org/). Overall, IBD has been shown to be well recorded in the CPRD. Diagnostic codes for UC and CD were both shown to have a positive predictive value of 92% among patients with prevalent disease (24). In another validation study, 92% of the IBD codes were supported by gastroenterology consultations, surgery, endoscopy, barium studies, or intestinal biopsy (23). In addition, the time interval between the date of incident IBD diagnosis reported by the general practitioner participating in the survey and the date recorded in the CPRD was less than 30 days in two-thirds of the cases (23). Finally, 87% of the first-ever IBD diagnoses recorded in the CPRD have been shown to be incident cases (25). Statistical analysis
Descriptive statistics were used to summarize the characteristics of the cohort, overall as well as separately for patients exposed and unexposed to ADT in the first 6 months of follow-up. Crude incidence rates for all IBD, UC, and CD were estimated by dividing the total number of events by the total number of person-years of follow-up, with 95% confidence intervals based on a Poisson distribution. Cox proportional hazards models using a time-varying exposure definition were used to estimate hazard ratios and 95% confidence intervals for all IBD, UC, and CD associated with the use of ADT, when compared with nonuse. This was considered the primary analysis. All model results were adjusted for the following potential confounders, measured at cohort entry: age (years), calendar year of cohort entry, smoking status (categorized as former, current, or never smoker), BMI (weight (kg)/height (m)2), prostate-specific antigen level (ng/mL), and use of nonsteroidal antiinflammatory drugs in the year before cohort entry. Variables with missing information were coded as “unknown.” Secondary analyses
Exposure assessment
Exposure to ADT consisted of gonadotropin-releasing hormone (GnRH) agonists (leuprolide, buserelin, goserelin, triptorelin), oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide), estrogens (diethylstilbestrol, estramustine), and bilateral orchiectomy. A time-dependent exposure definition was used, which allowed patients to move from a period of nonexposure to a period of exposure. Given the persistent nature of the hypogonadism induced by ADT
We conducted 3 secondary analyses, all with nonuse of ADT as the reference category. First, we repeated the primary analysis to assess whether the incidence of all IBD, UC, and CD varied according to the use of specific types of ADT. Thus, for this analysis, use of ADT was further classified into 2 groups: GnRH agonists (alone or in combination with other ADT types) and other ADTs. In the other two analyses, we assessed whether there was effect modification by BMI and smoking status by including in the models terms Am J Epidemiol. 2016;184(1):15–22
Androgen Deprivation Therapy and Inflammatory Bowel Disease 17
for interaction between exposure and these variables, categorized as BMI
