1,3-Butadiene, styrene and selected outcomes among synthetic rubber polymer workers: Updated exposure-response analyses.

OBJECTIVE: - To evaluate exposure-response relationships between 1,3-butadiene and styrene and selected diseases among synthetic rubber polymer workers. METHODS: - 21,087 workers (16,579 men; 4508 women) were followed from 1943 through 2009 to determine mortality outcomes. Cox regression models estimated rate ratios (RRs) and 95% confidence intervals (CIs) by quartile of cumulative exposure to butadiene or styrene and exposure-response trends for cancers of the bladder, lung, kidney, esophagus and pancreas, and for all nonmalignant respiratory disease (NMRD), chronic obstructive pulmonary disease (COPD) and pneumonia. RESULTS: - Bladder cancer RRs were 2.13 (95% CI = 1.03 to 4.41) and 1.64 (95% CI = 0.76 to 3.54) in the highest quartiles of cumulative exposure to butadiene and styrene, respectively, and exposure-response trends were positive for both monomers (butadiene, trend p = 0.001; styrene, trend p = 0.004). Further analyses indicated that the exposure-response effect of each monomer on bladder cancer was demonstrated clearly only in the subgroup with high cumulative exposure (at or above the median) to the other monomer. Lung cancer was not associated with either monomer among men. Among women, lung cancer RRs were above 1.0 in each quartile of cumulative exposure to each monomer, but exposure-response was not seen for either monomer. Male workers had COPD RRs slightly above 1.0 in each quartile of cumulative exposure to each monomer, but there was no evidence of exposure-response among the exposed. Monomer exposure was not consistently associated with COPD in women or with the other cancer outcomes. CONCLUSIONS: - This study found a positive exposure-response relationship between monomer exposures and bladder cancer. The independent effects of butadiene and styrene on this cancer could not be delineated. In some analyses, monomer exposure was associated with lung cancer in women and with COPD in men, but inconsistent exposure-response trends and divergent results by sex do not support a causal interpretation of the isolated positive associations.

1,3-Butadiene, styrene and lymphohaematopoietic cancers among North American synthetic rubber polymer workers: exposure-response analyses.

OBJECTIVE: To evaluate exposure-response between 1,3-butadiene, styrene and lymphohaematopoietic cancers in an updated cohort of workers at six North American plants that made synthetic rubber polymers. METHODS: Employees were followed from 1943 through 2009 to determine mortality outcomes. Cox regression analyses estimated rate ratios (RRs) and 95% CIs by quartile of cumulative exposure to butadiene or styrene, measured in parts per million-years (ppm-years), and exposure-response trends for all leukaemia, lymphoid leukaemia, myeloid leukaemia, acute myeloid leukaemia, non-Hodgkin's lymphoma (NHL), multiple myeloma and all B-cell malignancies. RESULTS: Among 21 087 workers, adjusted RRs for butadiene and all leukaemia (132 deaths) rose with increasing exposure, with an RR of 2.53 (95% CI 1.37 to 4.67) in the highest exposure quartile (≥363.64 ppm-years), and the exposure-response trend was statistically significant for all leukaemia (p=0.014) and for lymphoid leukaemia (52 deaths, p=0.007). Styrene exposure-response trends for all leukaemia and lymphoid leukaemia were less consistent than those for butadiene. Cumulative exposures to butadiene and styrene were not associated consistently with myeloid leukaemias or the B-cell malignancies, NHL and multiple myeloma. CONCLUSIONS: We confirmed a positive exposure-response relationship between butadiene and all leukaemia among workers, most of whom had coexposure to styrene. Results supported an association between butadiene and lymphoid leukaemia, but not myeloid leukaemia, and provided little evidence of any association of butadiene or styrene exposures with major subtypes of B-cell malignancies other than lymphoid leukaemia, including NHL and multiple myeloma.

Case-control study of brain and other central nervous system cancer among workers at semiconductor and storage device manufacturing facilities.

OBJECTIVE: This study evaluated the relationship between brain and other central nervous system cancer ('CNS cancer') and exposures at two semiconductor and electronic module manufacturing facilities and at a storage device manufacturing facility. METHODS: The case-control study, nested in a cohort of 126 836 employees, compared 120 CNS cancer cases and 1028 matched controls with respect to employment in 10 process groups and estimated cumulative exposure to 31 known or possible carcinogens. RESULTS: CNS cancer was associated with module manufacturing operations at two facilities. Module manufacturing is a process that begins with production of ceramic substrates followed by attachment of completed semiconductor chips and metal-containing circuitry resulting in a high performing electronic device. Positive associations with the highest tertile of estimated cumulative exposure were found for several chemicals, including 2-butoxyethanol, cyclohexanone, ortho-dichlorobenzene, cadmium, molybdenum, trichloroethylene and vinyl chloride. CONCLUSIONS: Results suggested positive associations between CNS cancer and specific operations and chemicals experienced in the semiconductor and electronic module manufacturing industry. However, lack of external support for these findings precludes a causal interpretation, and the observed associations may have been due to chance.

Duration of Bisphosphonate Drug Holidays and Associated Fracture Risk.

BACKGROUND: Discontinuation of bisphosphonates (BP) or a "drug holiday" after several years of treatment is increasingly common. However, the association of drug holiday duration with future fracture risk is unclear. OBJECTIVES: We evaluated the rate of fracture in relation to various lengths of drug holidays among women receiving long-term BP therapy. RESEARCH DESIGN: Observational cohort study using US Medicare data 2006-2016. Incidence rates (IRs) and Cox proportional hazards models were used to evaluate the rate and adjusted hazard ratios (aHRs) controlling for potential confounders. SUBJECTS: Women aged 65 years and above enrolled in fee-for-service Medicare who had been adherent (≥80%) to alendronate, risedronate, or zoledronate for ≥3 years. MEASURES: Hip, humerus, distal forearm, and clinical vertebral fracture. RESULTS: Among 81,427 eligible women observed for a median (interquartile range) of 4.0 (2.5, 5.3) years, 28% of women underwent a drug holiday. In the alendronate cohort (73% overall), the IR of hip fracture among women who discontinued BP for >2 years was 13.2 per 1000 person-years. Risk was increased (aHR=1.3, 1.1-1.4) versus continuing therapy (IR=8.8, referent). Rates were elevated for humerus fracture with discontinuation >2 years (aHR=1.3, 1.1-1.66) and for clinical vertebral fracture with discontinuation >2 years (aHR=1.2, 1.1-1.4). Results were similar for risedronate, zoledronate, and ibandronate for hip and clinical vertebral fracture. CONCLUSION: Discontinuing alendronate beyond 2 years was associated with increased risk of hip, humerus, and clinical vertebral fractures.

Temporal Trends and Factors Associated with Bisphosphonate Discontinuation and Restart.

Adverse events related to long-term use of bisphosphonates have raised interest in temporary drug discontinuation. Trends in bisphosphonate discontinuation and restart, as well factors associated with these decisions, are not fully understood at a population level. We investigated temporal trends of bisphosphonate discontinuation from 2010 to 2015 and identified factors associated with discontinuation and restart of osteoporosis therapy. Our cohort consisted of long-term bisphosphonate users identified from 2010 to 2015 Medicare data. We defined discontinuation as ≥12 months without bisphosphonate prescription claims. We used conditional logistic regression to compare factors associated with alendronate discontinuation or osteoporosis therapy restart in the 120-day period preceding discontinuation or restart referent to the 120-day preceding control periods. Among 73,800 long-term bisphosphonate users, 59,251 (80.3%) used alendronate, 6806 (9.2%) risedronate, and 7743 (10.5%) zoledronic acid, exclusively. Overall, 26,281 (35.6%) discontinued bisphosphonates for at least 12 months. Discontinuation of bisphosphonates increased from 1.7% in 2010, reaching a peak of 14% in 2012 with levels plateauing through 2015. The factors most strongly associated with discontinuation of alendronate were: benzodiazepine prescription (adjusted odds ratio [aOR] = 2.5; 95% confidence interval [CI] 2.1, 3.0), having a dual-energy X-ray absorptiometry (DXA) scan (aOR = 1.8; 95% CI 1.7, 2.0), and skilled nursing facility care utilization (aOR = 1.8; 95% CI 1.6, 2.1). The factors most strongly associated with restart of osteoporosis therapy were: having a DXA scan (aOR = 9.9; 95% CI 7.7, 12.6), sustaining a fragility fracture (aOR = 2.8; 95% CI 1.8, 4.5), and an osteoporosis or osteopenia diagnosis (aOR = 2.5; 95% CI 2.0, 3.1). Our national evaluation of bisphosphonate discontinuation showed that an increasing proportion of patients on long-term bisphosphonate therapy discontinue medications. The factors associated with discontinuation of alendronate were primarily related to worsening of overall health status, whereas traditional factors associated with worsening bone health were associated with restarting osteoporosis medication. © 2019 American Society for Bone and Mineral Research.

Mortality Among Men and Women in the North American Synthetic Rubber Industry, 1943 to 2009.

OBJECTIVE: To evaluate 1943 to 2009 mortality among 22,785 synthetic rubber industry employees. METHODS: Standardized mortality ratio (SMR) and internal Cox regression analyses. RESULTS: Among hourly employees with more than or equal to 10 years worked and more than or equal to 20 years since hire, SMRs were elevated for leukemia (SMR = 139, 95% confidence interval [CI] = 106 to 179), non-Hodgkin lymphoma (NHL) (SMR = 136, CI = 102 to 177), bladder cancer (SMR = 148, CI = 110 to 195) and, for women only, lung cancer (SMR = 225, CI = 103 to 427). Butadiene and styrene exposure-response trends were positive for leukemia and bladder cancer but not for NHL or for lung cancer among women. CONCLUSIONS: Results support a causal relationship between butadiene and leukemia. Interpretation of results for lung cancer among women and for bladder cancer is uncertain because of inability to control for smoking and inadequate or inconsistent support from other studies for an association between butadiene or styrene and the latter cancers.

The Design and Validation of a New Algorithm to Identify Incident Fractures in Administrative Claims Data.

Our study validated a claims-based algorithm for the identification of incident and recurrent fractures in administrative data. We used Centers for Medicare and Medicaid (CMS) claims from 2005 to 2014 linked to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) database. Case qualifying (CQ) fractures were identified among participants with ≥12 months of fee-for-service coverage before first fracture claim and ≥6 months after. Recurrent fractures were defined as the first CQ fracture that occurred following a clean period of at least 90 days from the last claim associated with the preceding incident fracture. We used medical records (discharge summary, imaging, and surgical report) to adjudicate fractures. We calculated positive predictive values (PPVs) for incident and recurrent fractures. Our study was not designed to assess the algorithm sensitivity or negative predictive value. We identified 2049 potential incident fractures from claims among 1650 participants. Record retrieval was attempted for 728 (35.5%) suspected incident fractures (prioritizing more recent CQ fractures associated with osteoporosis, but without explicitly requiring any osteoporosis ICD-9 diagnosis code). Our final sample included 520 claims-identified fractures with medical records, of which 502 (96.5%) were confirmed. The PPVs (95% CI) of the hip, wrist, humerus, and clinical vertebra-all exceeded 95%. We identified 117 beneficiaries with 292 ≥2 CQ fracture episodes at the same site, and attempted retrieval on 105 (36.0%) episodes. Our analytic sample included 72 (68.5%) CQ episodes from 33 participants. The PPVs for identifying recurrent clinical vertebral, hip/femur, and nonvertebral fractures with a 90-day clean period exceeded 95%. Although we could not ascertain sensitivity, our updated fracture identification algorithms had high PPV for the identification of incident and recurrent fractures of the same site. Although medical record review and clinical adjudication remain a gold standard, our claims-based algorithm provides an alternative approach to fracture ascertainment when high PPV is desired. © 2019 American Society for Bone and Mineral Research.

Retrospective Exposure Assessment for Semiconductor and Storage Device Manufacturing Facilities.

OBJECTIVE: The aim of this study was to develop exposure estimates for a case-control study of central nervous system cancer in semiconductor and storage device manufacturing workers. METHODS: Over 700,000 records on sample measurements were obtained. Mean exposure intensity was estimated for 31 established/suspected carcinogens (agents of interest) in 10 primary exposure groups over three manufacturing eras. We assigned confidence ratings, based on number/type of measurements, to each estimate. RESULTS: Mean exposures decreased by an order of magnitude over the three manufacturing eras and were below applicable occupational exposure limits for 22 of 31 agents of interest. For 25 agents, at least 70% of the exposures were estimated with high confidence. CONCLUSION: This is the largest comprehensive study of exposures in the semiconductor/storage device industry and the first to include cumulative exposure estimates and measures of confidence in the exposure estimates.

Building global partnerships through shared curricula for an MPH programme in India and Sri Lanka.

OBJECTIVE: To design and implement a locally relevant competency- based MPH programme. METHODS: The demand for trained public health professionals in South Asia is enormous and growing, which created a unique opportunity for a Fogarty International Center-funded University of Alabama at Birmingham-South Asia [Aga Khan University, Pakistan; Manipal Academy of Higher Education, India; and University of Kelaniya, Sri Lanka] international research training in environmental and occupational health (ITREOH) programme. In 2009, a Master of Public Health (MPH) degree programme was designed using a combination of competencies developed by the Association of School of Public Health, the World Health Organization and the Centers for Disease Control and Prevention. RESULTS: A competency- based curriculum was developed with two specialty tracks in applied epidemiology and environmental and occupational health, emphasising applied practice and research. CONCLUSIONS: This is the most comprehensive skill-based MPH programme in the region, which positions each institution as a regional leader in public health training. The success of the programme has been amply demonstrated by placements of graduated MPH students in leadership roles in public, private and academic sectors within their countries.

A systematic review of epidemiologic studies of styrene and cancer.

Previous epidemiology reviews of exposure to styrene and the risk of cancer considered studies published through 13 November 2013. Since then, additional relevant research has been published. No review has included meta-analyses. The current systematic review considered research published through June 2017; included meta-analyses of the relationship between any exposure to styrene and cancers identified as being of concern, including non-Hodgkin lymphoma (NHL), leukemia and cancers of the esophagus, pancreas, lung and kidney; and evaluated several other forms of cancer. Meta-relative risks for all studies were 1.14 (95% confidence interval (CI), 0.91-1.43) for NHL, 1.00 (95% CI, 0.80-1.26) for multiple myeloma, 0.98 (95% CI, 0.87-1.09) for all leukemia, 1.03 (95% CI, 0.92-1.15) for esophageal cancer, 1.02 (95% CI, 0.93-1.12) for pancreatic cancer, 1.09 (95% CI, 0.95-1.24) for lung cancer and 1.10 (95% CI, 0.99-1.22) for kidney cancer. Individual studies provided little evidence of exposure-response or induction time trends. Limitations of the available research and of the meta-analyses included reliance in most studies on mortality data rather than on incidence data, lack of quantitative estimates of styrene exposure for individual subjects and lack of information on lifestyle factors. Consideration of all pertinent data, including substantial recent research, indicates that the epidemiologic evidence on the potential carcinogenicity of styrene is inconclusive and does not establish that styrene causes any form of cancer in humans.

Accuracy of Medicare Claim-based Algorithm to Detect Breast, Prostate, or Lung Cancer Bone Metastases.

BACKGROUND: We had previously developed an algorithm for Medicare claims data to detect bone metastases associated with breast, prostate, or lung cancer. This study was conducted to examine whether this algorithm accurately documents bone metastases on the basis of diagnosis codes in Medicare claims data. METHODS: We obtained data from Medicare claims and electronic medical records of patients 65 years or older with a breast, prostate, or lung cancer diagnosis at a teaching hospital and/or affiliated clinics during 2005 or 2006. We calculated the sensitivity and positive predictive value (PPV) of our algorithm using medical records as the "gold standard." The κ statistic was used to measure agreement between claims and medical record data. RESULTS: The agreement between claims and medical record data for bone metastases among breast, prostate, and lung cancer patients was 0.93, 0.90, and 0.69, respectively. The sensitivities of our algorithm for bone metastasis in patients with breast, prostate, and lung were 96.8% [95% confidence interval (CI)=83.8% to 99.4%], 91.7% (95% CI=78.2% to 97.1%), and 74.1% (95% CI=55.3% to 86.8%), respectively; and the PPVs were 90.9% (95% CI=76.4% to 96.9%), 91.7% (95% CI=78.2% to 97.1%), and 71.4% (95% CI=52.9% to 84.8%), respectively. CONCLUSIONS: The algorithm for detecting bone metastases in claims data had high sensitivity and PPV for breast and prostate cancer patients. Sensitivity and PPV were lower but still moderate for lung cancer patients.

Improving medical record retrieval for validation studies in Medicare data.

PURPOSE: The purpose of the study is to describe medical record retrieval for a study validating claims-based algorithms used to identify seven adverse events of special interest (AESI) in a Medicare population. METHODS: We analyzed 2010-2011 Medicare claims of women with postmenopausal osteoporosis and men ≥65 years of age in the Medicare 5% national sample. The final cohorts included beneficiaries covered continuously for 12+ months by Medicare parts A, B, and D and not enrolled in Medicare Advantage before starting follow-up. We identified beneficiaries using each AESI algorithm and randomly selected 400 women and 100 men with each AESI for medical record retrieval. The Centers for Medicare and Medicaid Services provided beneficiary contact information, and we requested medical records directly from providers, without patient contact. RESULTS: We selected 3331 beneficiaries (women: 2272; men: 559) for whom we requested 3625 medical records. Overall, we received 1738 [47.9% (95%CI 46.3%, 49.6%)] of the requested medical records. We observed small differences in the characteristics of the total population with AESIs compared with those randomly selected for retrieval; however, no differences were seen between those selected and those retrieved. We retrieved 54.7% of records requested from hospitals compared with 26.3% of records requested from physician offices (p < 0.001). Retrieval did not differ by sex or vital status of the beneficiaries. CONCLUSIONS: Our national medical record validation study of claims-based algorithms produced a modest retrieval rate. The medical record procedures outlined in this paper could have led to the improved retrieval from our previous medical record retrieval study. Copyright © 2016 John Wiley & Sons, Ltd.

Systematic review and meta-analysis of glyphosate exposure and risk of lymphohematopoietic cancers.

This systematic review and meta-analysis rigorously examines the relationship between glyphosate exposure and risk of lymphohematopoietic cancer (LHC) including NHL, Hodgkin lymphoma (HL), multiple myeloma (MM), and leukemia. Meta-relative risks (meta-RRs) were positive and marginally statistically significant for the association between any versus no use of glyphosate and risk of NHL (meta-RR = 1.3, 95% confidence interval (CI) = 1.0-1.6, based on six studies) and MM (meta-RR = 1.4, 95% CI = 1.0-1.9; four studies). Associations were statistically null for HL (meta-RR = 1.1, 95% CI = 0.7-1.6; two studies), leukemia (meta-RR = 1.0, 95% CI = 0.6-1.5; three studies), and NHL subtypes except B-cell lymphoma (two studies each). Bias and confounding may account for observed associations. Meta-analysis is constrained by few studies and a crude exposure metric, while the overall body of literature is methodologically limited and findings are not strong or consistent. Thus, a causal relationship has not been established between glyphosate exposure and risk of any type of LHC.

Agreement between Medicare pharmacy claims, self-report, and medication inventory for assessing lipid-lowering medication use.

BACKGROUND: Medicare claims have been used to study lipid-lowering medication (LLM) use among US adults. METHODS: We analyzed the agreement between Medicare claims for LLM and LLM use indicated by self-report during a telephone interview and, separately, by a medication inventory performed during an in-home study visit upon enrollment into the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. We included REGARDS participants ≥65 years enrolled in 2006-2007 with Medicare pharmacy benefits (Part D) from 120 days before their telephone interview through their medication inventory (n = 899). RESULTS: Overall, 39.2% and 39.5% of participants had a Medicare claim for an LLM within 120 days prior to their interview and medication inventory, respectively. Also, 42.7% of participants self-reported using LLMs, and 41.8% had an LLM in their medication inventory. The Kappa statistic (95% confidence interval [CI]) for agreement of Medicare claims with self-report and medication inventory was 0.68 (0.63-0.73) and 0.72 (0.68-0.77), respectively. No Medicare claims for LLMs were present for 22.1% (95%CI: 18.1-26.6%) of participants who self-reported taking LLMs and 18.9% (15.1-23.3%) with LLMs in their medication inventory. Agreement between Medicare claims and self-report was lower among Black male individuals (Kappa = 0.34 [95%CI: 0.14-0.54]) compared with Black female individuals (0.70 [0.61-0.79]), White male individuals (0.65 [0.56-0.75]), and White female individuals (0.79 [0.72-0.86]). Agreement between Medicare claims and the medication inventory was also low among Black male individuals (Kappa = 0.48 [95%CI: 0.29-0.66]). CONCLUSIONS: Although substantial agreement exists, many Medicare beneficiaries who self-report LLM use or have LLMs in a medication inventory have no claims for these medications. Copyright © 2016 John Wiley & Sons, Ltd.

Association of hyperlipidaemia, inflammation and serological status and coronary heart disease among patients with rheumatoid arthritis: data from the National Veterans Health Administration.

OBJECTIVE: To examine the association of serum lipids, inflammation and seropositivity on coronary heart disease (CHD) and stroke in patients with rheumatoid arthritis (RA). METHODS: The incidence of hospitalised myocardial infarction (MI) or stroke was calculated in a cohort of patients with RA receiving care within the national Veterans Health Administration from 1998 to 2011. Cox proportional hazard models were used to examine the association between these outcomes and low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as time-varying variables, divided into quintiles. RESULTS: There were 37,568 patients with RA in the cohort with mean age of 63 years (SD 12.1); 90% were men. There was a no clear association between LDL-C and CHD/stroke. Compared with lower HDL-C (<34 mg/dL), higher HDL-C (≥54 mg/dL) was inversely associated with MI (hazard ratio (HR)=0.68, 95% CI 0.55 to 0.85) and stroke (HR=0.69, 95% CI 0.50 to 0.96). Higher CRP >2.17 mg/dL (vs CRP <0.26 mg/dL) was associated with increased risk (HR=2.43, 95% CI 1.77 to 3.33) for MI and 2.02 (95% CI 1.32 to 3.08) for stroke. ESR >47 mm/h compared with <8 mm/h had an HR 1.87 (95% CI 1.39 to 2.52) for MI and 2.00 (95% CI 1.26 to 3.18) for stroke. The association between MI was significant for RA seropositivity (HR=1.23, 95% CI 1.03 to 1.48). CONCLUSIONS: In this predominantly older male RA cohort, there was no clear association between LDL-C and CHD, whereas higher HDL-C was inversely associated with MI and stroke. CRP and ESR were similarly associated with increase MI risk and stroke, reflecting the prominent role of inflammation in CHD risk in RA.

Comparative Risk of Hospitalized Infection Associated With Biologic Agents in Rheumatoid Arthritis Patients Enrolled in Medicare.

OBJECTIVE: The risks of hospitalized infection associated with biologic agents used to treat rheumatoid arthritis (RA) are unclear. The aim of this study was to determine whether the associated risk of hospitalized infections differed between specific biologic agents used to treat RA. METHODS: In a retrospective cohort study using Medicare data from 2006-2011 for all enrolled patients with RA, new episodes of treatment with etanercept, adalimumab, certolizumab, golimumab, infliximab, abatacept, rituximab, and tocilizumab were identified. Patients were required to have received another biologic agent previously and to have been continuously enrolled in Medicare medical and pharmacy plans during the baseline period and throughout followup. Followup started on the date of initiation of treatment with the new biologic agent (after previous treatment with a different biologic agent) and ended on the date of the earliest hospitalized infection, at 12 months, after an exposure gap of >30 days, or at the time of death or loss of Medicare coverage. Cox regression analysis was used to calculate the adjusted hazard ratio (HR) for hospitalized infection, adjusting for an infection risk score and other confounders. RESULTS: Of 31,801 new biologic treatment episodes in patients who had previously received another biologic agent, 12.0% were with etanercept, 15.2% with adalimumab, 5.9% with certolizumab, 4.4% with golimumab, 12.4% with infliximab, 28.9% with abatacept, 14.8% with rituximab, and 6.3% with tocilizumab. During followup, we identified 2,530 hospitalized infections; incidence rates ranged from 13.1 per 100 person-years (abatacept) to 18.7 per 100 person-years (rituximab). After adjustment, etanercept (HR 1.24, 95% confidence interval [95% CI] 1.07-1.45), infliximab (HR 1.39, 95% CI 1.21-1.60), and rituximab (HR 1.36, 95% CI 1.21-1.53) had significantly higher HRs for hospitalized infection compared with abatacept. CONCLUSION: In RA patients with prior exposure to a biologic agent, exposure to etanercept, infliximab, or rituximab was associated with a greater 1-year risk of hospitalized infection compared with the risk associated with exposure to abatacept.

1,3-Butadiene, styrene and lymphohematopoietic cancer among male synthetic rubber industry workers--Preliminary exposure-response analyses.

We updated the mortality experience of North American synthetic rubber industry workers to include follow-up from 1944 through 2009, adding 11 years of mortality data to previous investigations. The present analysis used Cox regression to examine the exposure-response relationship between 1,3-butadiene (BD) and styrene (STY) parts per million (ppm)-years and leukemia (N = 114 deaths), non-Hodgkin lymphoma (NHL) (N = 89) and multiple myeloma (MM) (N = 48). A pattern of largely monotonically increasing rate ratios across deciles of BD ppm-years and a positive, statistically significant exposure-response trend were observed for BD ppm-years and leukemia. Using continuous, untransformed BD ppm-years the regression coefficient (ß) adjusted only for age was 2.6 × 10(-4) (p < 0.01); the regression coefficient adjusted for age, year of birth, race and plant was 2.9 × 10(-4) (p < 0.01). STY ppm-years also displayed a positive exposure-response association with leukemia. STY and BD were strongly correlated, and the separate effects of these two agents could not be estimated. For NHL, a pattern of approximately monotonically increasing rate ratios across deciles of exposure was seen for STY but not for BD; the test of trend was statistically significant in one of five models that used different STY exposure metrics and adjusted for age and other covariates. BD ppm-years and STY ppm-years were not associated with MM. The present analyses indicated a positive exposure-response relationship between BD cumulative exposure and leukemia. This result along with other research and biological information support an interpretation that BD causes leukemia in humans. STY exposure also was positively associated with leukemia, but its independent effect could not be delineated because of its strong correlation with BD, and there is no external support for a STY-leukemia association. STY, but not BD, was associated positively with NHL. The interpretation of this result is uncertain because the exposure-response data were statistically imprecise and because consistent support for causality from other studies is lacking. The current study provides no support for an association between BD or STY and MM.

The comparative effectiveness of biologics among older adults and disabled rheumatoid arthritis patients in the Medicare population.

AIMS: Older and disabled rheumatoid arthritis (RA) patients are often not present in large numbers in clinical trials or registries. A novel, claims-based clinical effectiveness algorithm provides the potential to compare the effectiveness of different biologics among this population using large administrative databases. METHOD: Using Medicare 2006-2010 data for 100% of patients with RA, we identified biologic naïve users of abatacept, adalimumab, etanercept and infliximab, defined as no biologic use during the 12 months before the biologic initiation. The effectiveness was evaluated at 365 days after biologic initiation, determined using a validated claims-based algorithm. We compared the proportion meeting effectiveness criteria for each biologic using robust Poisson regression to compute risk ratios (RRs) adjusted for potential confounders. One year cost per effectively treated patient was calculated by different biologics. RESULTS: The study included biologic naïve users of abatacept (n = 2129), adalimumab (n = 2944), etanercept (n = 3517) and infliximab (n = 5654). The algorithm classified the medications as 26% effective for abatacept, 24% for adalimumab, 28% for etanercept and 23% for infliximab, indicating comparable effectiveness. However, after adjustment and compared with infliximab, the RRs for effectiveness were 1.17 (95% CI 1.06, 1.30) for abatacept, 1.11 (95% CI 1.02, 1.23) for adalimumab and 1.27 (95% CI 1.17, 1.39) for etanercept. Older patients had a higher effectiveness than patients who were disabled (RR = 1.18, 95% CI 1.08, 1.28). Infliximab had highest cost per effectively treated patient. CONCLUSION: Abatacept, adalimumab and etanercept are more effective than infliximab among RA patients initiating biologics. Effectiveness was significantly higher among older patients compared with disabled RA Medicare patients.

The Validity of Claims-Based Algorithms to Identify Serious Hypersensitivity Reactions and Osteonecrosis of the Jaw.

Validation of claims-based algorithms to identify serious hypersensitivity reactions and osteonecrosis of the jaw has not been performed in large osteoporosis populations. The objective of this project is to estimate the positive predictive value of the claims-based algorithms in older women with osteoporosis enrolled in Medicare. Using the 2006-2008 Medicare 5% sample data, we identified potential hypersensitivity and osteonecrosis of the jaw cases based on ICD-9 diagnosis codes. Potential hypersensitivity cases had a 995.0, 995.2, or 995.3 diagnosis code on emergency department or inpatient claims. Potential osteonecrosis of the jaw cases had ≥1 inpatient or outpatient physician claim with a 522.7, 526.4, 526.5, or 733.45 diagnosis code or ≥2 claims of any type with a 526.9 diagnosis code. All retrieved records were redacted and reviewed by experts to determine case status: confirmed, not confirmed, or insufficient information. We calculated the positive predictive value as the number of confirmed cases divided by the total number of retrieved records with sufficient information. We requested 412 potential hypersensitivity and 304 potential osteonecrosis of the jaw records and received 174 (42%) and 84 (28%) records respectively. Of 84 potential osteonecrosis of the jaw cases, 6 were confirmed, resulting in a positive predictive value (95% CI) of 7.1% (2.7, 14.9). Of 174 retrieved potential hypersensitivity records, 95 were confirmed. After exclusion of 25 records with insufficient information for case determination, the overall positive predictive value (95% CI) for hypersensitivity reactions was 76.0% (67.5, 83.2). In a random sample of Medicare data, a claim-based algorithm to identify serious hypersensitivity reactions performed well. An algorithm for osteonecrosis of the jaw did not, partly due to the inclusion of diagnosis codes that are not specific for osteoporosis of the jaw.

Effectiveness and Safety of Immunomodulators With Anti-Tumor Necrosis Factor Therapy in Crohn's Disease.

BACKGROUND & AIMS: The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD. METHODS: We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared by using 3 metrics of effectiveness-surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery-and 2 metrics of safety-serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses. RESULTS: Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR], 1.20; 95% confidence interval, 0.73-1.96), hospitalization (HR, 0.82; 0.57-1.19), discontinuation of anti-TNF therapy or surgery (HR, 1.09; 0.88-1.34), and serious infection (HR, 0.93; 0.88-1.34) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risks of opportunistic infection (HR, 2.64; 1.21-5.73) and herpes zoster (HR, 3.16; 1.25-7.97) were increased with combination therapy. CONCLUSIONS: We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.