Lisa J. Herrinton

Initiation of Tumor Necrosis Factor-α Antagonists and the Risk of Hospitalization for Infection in Patients With Autoimmune Diseases

CONTEXT Although tumor necrosis factor (TNF)-α antagonists are increasingly used in place of nonbiologic comparator medications, their safety profile remains incomplete. OBJECTIVES To determine whether initiation of TNF-α antagonists compared with nonbiologic comparators is associated with an increased risk of serious infections requiring hospitalization. DESIGN, SETTING, AND PATIENTS Within a US multi-institutional collaboration, we assembled retrospective cohorts (1998-2007) of patients with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis, psoriatic arthritis, or ankylosing spondylitis (psoriasis and spondyloarthropathies) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid, and national Medicaid/Medicare. TNF-α antagonists and nonbiologic regimens were compared in disease-specific propensity score (PS)-matched cohorts using Cox regression models with nonbiologics as the reference. Baseline glucocorticoid use was evaluated as a separate covariate. MAIN OUTCOME MEASURE Infections requiring hospitalization (serious infections) during the first 12 months after initiation of TNF-α antagonists or nonbiologic regimens. RESULTS Study cohorts included 10,484 RA, 2323 IBD, and 3215 psoriasis and spondyloarthropathies matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1172 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among patients with RA, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR], 1.05 [95% CI, 0.91-1.21]). Among patients with IBD, rates were 10.91 (TNF-α antagonists) and 9.60 (comparator) per 100 person-years (aHR, 1.10 [95% CI, 0.83-1.46]). Among patients with psoriasis and spondyloarthropathies, rates were 5.41 (TNF-α antagonists) and 5.37 (comparator) per 100 person-years (aHR, 1.05 [95% CI, 0.76-1.45]). Among patients with RA, infliximab was associated with a significant increase in serious infections compared with etanercept (aHR, 1.26 [95% CI, 1.07-1.47]) and adalimumab (aHR, 1.23 [95% CI, 1.02-1.48]). Baseline glucocorticoid use was associated with a dose-dependent increase in infections. CONCLUSION Among patients with autoimmune diseases, compared with treatment with nonbiologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.

Efficacy of Prophylactic Mastectomy in Women With Unilateral Breast Cancer: A Cancer Research Network Project

PURPOSE We investigated the efficacy of contralateral prophylactic mastectomy (CPM) in reducing contralateral breast cancer incidence and breast cancer mortality among women who have already been diagnosed with breast cancer. METHODS This retrospective cohort study comprised approximately 50,000 women who were diagnosed with unilateral breast cancer during 1979 to 1999. Using computerized data confirmed by chart review, we identified 1,072 women (1.9%) who had CPM. We obtained covariate information for these women and for a sample of 317 women who did not undergo CPM. RESULTS The median time from initial breast cancer diagnosis to the end of follow-up was 5.7 years. Contralateral breast cancer developed in 0.5% of women with CPM, metastatic disease developed in 10.5%, and subsequent breast cancer developed in 12.4%; 8.1% died from breast cancer. Contralateral breast cancer developed in 2.7% of women without CPM, and 11.7% died of breast cancer. After adjustment for initial breast cancer characteristics, treatment, and breast cancer risk factors, the hazard ratio (HR) for the occurrence of contralateral breast cancer after CPM was 0.03 (95% CI, 0.006 to 0.13). After adjustment for breast cancer characteristics and treatment, the HRs for the relationship of CPM with death from breast cancer, with death from other causes, and with all-cause mortality were 0.57 (95% CI, 0.45 to 0.72), 0.78 (95% CI, 0.57 to 1.06), and 0.60 (95% CI, 0.50 to 0.72), respectively. CONCLUSION CPM seems to protect against the development of contralateral breast cancer, and although women who underwent CPM had relatively low all-cause mortality, CPM also was associated with decreased breast cancer mortality.

Urine bisphenol-A (BPA) level in relation to semen quality

OBJECTIVE To determine whether urine bisphenol-A (BPA) levels are associated with lower semen quality. DESIGN Cohort study. SETTING Four regions in China where high exposure to BPA in the workplace existed. PATIENT(S) 218 men with and without BPA exposure in the workplace. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Semen parameters. RESULT(S) After adjustment for potential confounders using linear regression, increasing urine BPA level was statistically significantly associated with [1] decreased sperm concentration, [2] decreased total sperm count, [3] decreased sperm vitality, and [4] decreased sperm motility. Compared with men who did not have detectable urine BPA levels, those with detectable urine BPA had more than three times the risk of lowered sperm concentration and lower sperm vitality, more than four times the risk of lower sperm count, and more than twice the risk of lower sperm motility. The urine BPA level was not associated with semen volume or abnormal sperm morphology. Similar dose-response associations were observed among men with environmental BPA exposure at levels comparable with those in the U.S population. Despite a markedly reduced sample size, the inverse correlation between increased urine BPA levels and decreased sperm concentration and total sperm count remained statistically significant. CONCLUSION(S) These results provide the first epidemiologic evidence of an adverse effect of BPA on semen quality.

Occupational exposure to bisphenol-A (BPA) and the risk of Self-Reported Male Sexual Dysfunction

BACKGROUND Animal studies have suggested that bisphenol-A (BPA) is a potential human endocrine disrupter; but evidence from human studies is needed. METHODS We conducted an occupational cohort study to examine the effect of occupational exposure to BPA on the risk of male sexual dysfunction. Current workers from BPA-exposed and control factories were recruited. The exposed workers were exposed to very high BPA levels in their workplace. Male sexual function was ascertained through in-person interviews using a standard male sexual function inventory. RESULTS BPA-exposed workers had consistently higher risk of male sexual dysfunction across all domains of male sexual function than the unexposed workers. After controlling for matching variables and potential confounders, exposed workers had a significantly increased risk of reduced sexual desire [odds ratios (OR) = 3.9, 95% confidence interval: 1.8-8.6), erectile difficulty (OR = 4.5, 95% CI 2.1-9.8), ejaculation difficulty (OR = 7.1, 95% CI 2.9-17.6), and reduced satisfaction with sex life (OR = 3.9, 95% CI 2.3-6.6). A dose-response relationship was observed with an increasing level of cumulative BPA exposure associated with a higher risk of sexual dysfunction. Furthermore, compared with the unexposed workers, BPA-exposed workers reported significantly higher frequencies of reduced sexual function within 1 year of employment in the BPA-exposed factories. CONCLUSIONS Our findings provide the first evidence that exposure to BPA in the workplace could have an adverse effect on male sexual dysfunction.

Bisphenol A levels in blood and urine in a Chinese population and the personal factors affecting the levels

The objective of the study was to describe the background bisphenol A (BPA) levels in urine and serum of a Chinese population without occupational exposure and to examine the personal characteristics influencing these levels. Workers from 10 factories and their family members were recruited and their peripheral blood and spot urine samples were collected. The conjugated and free BPA of the samples was assayed with high-performance liquid chromatography. The exposure levels were checked with 2-independent-samples test, and the potential personal factors influencing exposure levels were analyzed using nonlinear correlation. Of the total of 952 subjects participating in the study, urine and blood samples were taken from 97% and 93% of them, respectively. The detectable rates were 50% for urine samples and 17% for serum samples, given the detection limit of 0.31 microg/L for urine and 0.39 microg/L for serum. The arithmetic mean (AM) and geometric mean (GM) of non-creatinine-adjusted urinary BPA level were 10.45 and 0.87 microg/L, which became 24.93 and 0.38 microg/g Cr after the creatinine level was adjusted; serum BPA levels were 2.84 microg/L (AM) and 0.18 microg/L (GM). Males and those with smoking habit had higher biological burden of BPA. The results indicated that half of the study subjects had detectable BPA in their urine samples. BPA levels were influenced by gender and smoking status. The sources of non-occupational BPA exposures should be explored.

Recent Declines in Hormone Therapy Utilization and Breast Cancer Incidence: Clinical and Population-Based Evidence

TO THE EDITOR: Long-term use of estrogen- or progestincontaining hormone therapies (HT) is well recognized to be associated with increased risk of breast cancer both in observational studies and the Women’s Health Initiative (WHI) randomized trial. 1 After the early termination of the trial in July 2002 and the subsequent media coverage, reports from clinical series indicated immediate declines of 28% to 46% in prevalences of HT and estrogen-only (ET) use. 2,3 The population-level impact of these declines on breast cancer are uncertain given the 2- to 3-year lag time between diagnosis and data availability in cancer registries. To better understand the possible impact from changes in HT on breast cancer in larger populations, we compared recent secular trends in HT use and breast cancer incidence in available clinical and population-based data resources, including recently released cancer registry data for the year 2004. We calculated the annual prevalence of HT use and the annual incidence of invasive breast cancer for the period from 1994 to 2003 for women ages 50 to 74 years in Kaiser Permanente’s (Oakland, CA) Northern California region (KPNC), a large integrated health-delivery system from which computerized pharmacy, membership, and hospital cancer registry data were obtained. Women filling at least two prescriptions (generally constituting 90 days per prescription) of HT or ET in any calendar year were considered users for that year. First primary invasive breast cancer (International Classification of Disease–Oncology, 3rd edition [ICDO-3] 4 site 50.0-50.9) diagnoses were identified, with histologic subtypes defined as ductal (ICD-O-3 codes 8500), or “with lobular component” (ICD-O-3 codes 8520, 8522, 8524). Yearly denominators included women who were KPNC members for at least 11 months of

Incidence and Mortality of Colorectal Adenocarcinoma in Persons With Inflammatory Bowel Disease From 1998 to 2010

BACKGROUND & AIMS The relationship between inflammatory bowel disease (IBD) and the incidence and mortality of colorectal adenocarcinoma (CRC) has not been evaluated recently. METHODS We calculated the incidence and standardized incidence and mortality rate ratios of CRC among adult individuals with intact colons using Kaiser Permanente of Northern Californias database of members with IBD and general membership data for the period of 1998 to June 2010 (data through 2008 were used to calculate mortality). We also evaluated trends in medication use and rates of cancer detection over time. RESULTS We identified 29 cancers among persons with Crohns disease (CD) and 53 among persons with ulcerative colitis (UC). Overall, the incidence rates of cancer among individuals with CD, UC, or in the general membership were 75.0, 76.0, and 47.1, respectively, per 100,000 person-years. In the general population, the incidence of CRC was 21% higher in 2007-2010 than in 1998-2001 (P for trend, <.0001), coincident with the growth of CRC screening programs. The incidence of CRC among individuals with CD or UC was 60% higher than in the general population (95% confidence interval [CI] for CD, 20%-200%; 95% CI for UC, 30%-200%) and was stable over time (P for trend was as follows: CD, .98; UC, .40). During 1998-2008, the standardized mortality ratio for CRC in individuals with CD was 2.3 (95% CI, 1.6-3.0) and 2.0 in those with UC (95% CI, 1.3-2.7). Over the study period, anti-tumor necrosis factor agents replaced other therapies for CD and UC; the rate of colonoscopy increased by 33% among patients with CD and decreased by 9% in those with UC. CONCLUSIONS From 1998 to 2010, the incidence of CRC in patients with IBD was 60% higher than in the general population and essentially stable over time.

Association Between the Initiation of Anti–Tumor Necrosis Factor Therapy and the Risk of Herpes Zoster

IMPORTANCE Herpes zoster reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates herpes zoster risk. OBJECTIVES To ascertain whether initiation of anti-TNF therapy compared with nonbiologic comparators is associated with increased herpes zoster risk. DESIGN, SETTING, AND PATIENTS We identified new users of anti-TNF therapy among cohorts of patients with RA, inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis from 1998 through 2007 within a large US multi-institutional collaboration combining data from Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and national Medicaid/Medicare programs. We compared herpes zoster incidence between new anti-TNF users (n=33,324) and patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs) (n=25,742) within each inflammatory disease cohort (last participant follow-up December 31, 2007). Within these cohorts, we used Cox regression models to compare propensity score-adjusted herpes zoster incidence between new anti-TNF and nonbiologic DMARD users while controlling for baseline corticosteroid use. MAIN OUTCOME MEASURES Incidence of herpes zoster cases occurring after initiation of new anti-TNF or nonbiologic DMARD therapy. RESULTS Among 33,324 new users of anti-TNF therapy, we identified 310 herpes zoster cases. Crude incidence rates among anti-TNF users were 12.1 per 1000 patient-years (95% CI, 10.7-13.6) for RA, 11.3 per 1000 patient-years (95% CI, 7.7-16.7) for inflammatory bowel disease, and 4.4 per 1000 patient-years (95% CI, 2.8-7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64-2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77-1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88-1.36). CONCLUSION AND RELEVANCE Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of herpes zoster compared with patients who initiated nonbiologic treatment regimens.

Incidence and Prevalence of Inflammatory Bowel Disease in a Northern California Managed Care Organization, 1996–2002

OBJECTIVE:There are few estimates of the incidence and prevalence of inflammatory bowel disease in North American communities. We sought to estimate the incidence and prevalence of inflammatory bowel disease (IBD), including Crohns disease (CD), and ulcerative colitis (UC), among 3.2 million members of Kaiser Permanente, Northern California, for the period 1996–2002.METHODS:All health plan members who had one or more diagnoses of CD (ICD-9 code 555) or UC (ICD-9 code 556) on computerized records during the period 1996–2002 and with at least 12 months of membership were identified as possible IBD cases (N = 12,059). We randomly sampled 24% of these for chart review to confirm the diagnosis and obtain the initial diagnosis date. Incidence rates and the point prevalence on December 31, 2002 were standardized to the 2000 U. S. Census.RESULTS:The annual incidence rate per 100,000 persons was 6.3 for CD (95% confidence interval [CI], 5.6–7.0) and 12.0 for UC (CI, 11.0–13.0). The point prevalence per 100,000 on December 31, 2002 was 96.3 for CD (95% CI, 89.6–103.0) and 155.8 for UC (95% CI, 146.6–164.9), increasing to 100.3 and 205.8 per 100,000, respectively, when hospital discharge data from 1985 to 1995 were included. The age-specific incidence of CD was bimodal, while UC incidence rose in early adulthood and remained elevated with advancing age.CONCLUSIONS:The incidence we estimated for CD was similar to the previous U. S. estimate. Our incidence estimate for UC was much higher than the previous U.S. estimate, but similar to that of recent Canadian and European studies. The prevalence we estimated for CD was somewhat lower than previous estimates.

Mycobacterial diseases and antitumour necrosis factor therapy in USA

Objective In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. Methods At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000–2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. Results Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). Conclusions Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.