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.

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.

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.

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.

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.

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.

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.

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.

Risk of hospitalised infection in rheumatoid arthritis patients receiving biologics following a previous infection while on treatment with anti-TNF therapy.

BACKGROUND: The risk of subsequent infections in rheumatoid arthritis (RA) patients who receive biologic therapy after a serious infection is unclear. OBJECTIVE: To compare the subsequent risk of hospitalised infections associated with specific biologic agents among RA patients previously hospitalised for infection while receiving anti-tumour necrosis factor (anti-TNF) therapy. METHODS: Using 2006-2010 Medicare data for 100% of beneficiaries with RA enrolled in Medicare, we identified patients hospitalised with an infection while on anti-TNF agents. Follow-up began 61 days after hospital discharge and ended at the earliest of: next infection, loss of Medicare coverage or 18 months after start of follow-up. We calculated the incidence rate of subsequent hospitalised infection for each biologic and used Cox regression to control for potential confounders. RESULTS: 10 794 eligible hospitalised infections among 10183 unique RA patients who contributed at least 1 day of biologic exposure during follow-up. We identified 7807 person-years of exposure to selected biologics--333 abatacept, 133 rituximab and 7341 anti-TNFs (1797 etanercept, 1405 adalimumab, 4139 infliximab)--and 2666 associated infections. Mean age across biologic exposure cohorts was 64-69 years. The crude incidence rate of subsequent hospitalised infection ranged from 27.1 to 34.6 per 100 person-years. After multivariable adjustment, abatacept (HR: 0.80, 95% CI 0.64 to 0.99) and etanercept (HR: 0.83, 95% CI 0.72 to 0.96) users had significantly lower risks of subsequent infection compared to infliximab users. CONCLUSIONS: Among RA patients who experienced a hospitalised infection while on anti-TNF therapy, abatacept and etanercept were associated with the lowest risk of subsequent infection compared to other biologic therapies.

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.

Fractures and mortality in relation to different osteoporosis treatments.

OBJECTIVES: Few studies have assessed the effectiveness of different drugs for osteoporosis (OP). We aimed to determine if fracture and mortality rates vary among patients initiating different OP medications. METHODS: We used the Medicare 5% sample to identify new users of intravenous (IV) zoledronic acid (n=1.674), oral bisphosphonates (n=32.626), IV ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or parathyroid hormone (n=549). We included beneficiaries who were ≥65 years of age, were continuously enrolled in fee-for-service Medicare and initiated therapy during 2007-2009. Outcomes were hip fracture, clinical vertebral fracture, and all-cause mortality, identified using inpatient and physician diagnosis codes for fracture, procedure codes for fracture repair, and vital status information. Cox regression models compared users of each medication to users of IV zoledronic acid, adjusting for multiple confounders. RESULTS: During follow-up (median, 0.8-1.5 years depending on the drug), 787 subjects had hip fractures, 986 had clinical vertebral fractures, and 2.999 died. Positive associations included IV ibandronate with hip fracture (adjusted hazard ratio (HR), 2.37; 95% confidence interval (CI) 1.25-4.51), calcitonin with vertebral fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality (HR=1.31; 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome comparisons were not statistically significant. CONCLUSIONS: IV ibandronate and calcitonin were associated with higher rates of some types of fracture when compared to IV zolendronic acid. The relatively high mortality associated with use of calcitonin may reflect the poorer health of users of this agent.

Comparative effectiveness of infliximab and adalimumab for Crohn's disease.

BACKGROUND & AIMS: Antibodies against tumor necrosis factor-α are widely used to treat patients with Crohn's disease (CD). This study compared the effectiveness of infliximab and adalimumab, the 2 most commonly used anti-tumor necrosis factor agents, in patients with CD. METHODS: We conducted a retrospective cohort study by using U.S. Medicare data from 2006 through 2010. Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871) after January 31, 2007, were included. Patients older than age 85 and those with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis were excluded. The primary outcome measures were disease persistence on therapy at week 26, surgery (including bowel resection, creation of an ostomy, or surgical treatment of a perforation or abscess), and hospitalization for CD. Propensity score-adjusted logistic and Cox regression were used to compute adjusted odds ratios or hazard ratios and 95% confidence intervals (CIs). RESULTS: After 26 weeks of treatment, 49% of patients receiving infliximab remained on drug, compared with 47% of those receiving adalimumab (odds ratio, 0.98; 95% CI, 0.81-1.19). Fewer patients treated with infliximab underwent surgery than those treated with adalimumab, but this difference was not statistically significant (5.5 vs 6.9 surgeries per 100 person-years; hazard ratio, 0.79; 95% CI, 0.60-1.05). Rates of hospitalization did not differ between groups (hazard ratio, 0.88; 95% CI, 0.72-1.07). CONCLUSIONS: We observed similar effectiveness of infliximab and adalimumab for CD on the basis of 3 clinically important outcome measures.

The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis.

OBJECTIVE: To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. METHODS: We conducted a retrospective cohort study using 2005-2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. RESULTS: We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP>10 mg/L compared with <1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR>42 mm/h compared with <14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol ≥60 mg/dL (1.6 mmol/L) compared with <40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. CONCLUSIONS: This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk.

Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) study.

OBJECTIVES: To determine among patients with autoimmune diseases in the USA whether the risk of non-viral opportunistic infections (OI) was increased among new users of tumour necrosis factor α inhibitors (TNFI), when compared to users of non-biological agents used for active disease. METHODS: We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease and psoriasis-psoriatic arthritis-ankylosing spondylitis patients during 1998-2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programmes for the elderly, Tennessee Medicaid and US Medicaid/Medicare programmes. We compared incidence of non-viral OI among new TNFI users and patients initiating non-biological disease-modifying antirheumatic drugs (DMARD) overall and within each disease cohort. Cox regression models were used to compare propensity-score and steroid- adjusted OI incidence between new TNFI and non-biological DMARD users. RESULTS: Within a cohort of 33 324 new TNFI users we identified 80 non-viral OI, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OI among new users of TNFI compared to those initiating non-biological DMARD was 2.7 versus 1.7 per 1000-person-years (aHR 1.6, 95% CI 1.0 to 2.6). Baseline corticosteroid use was associated with non-viral OI (aHR 2.5, 95% CI 1.5 to 4.0). In the RA cohort, rates of non-viral OI among new users of infliximab were higher when compared to patients newly starting non-biological DMARD (aHR 2.6, 95% CI 1.2 to 5.6) or new etanercept users (aHR 2.9, 95% CI 1.5 to 5.4). CONCLUSIONS: In the USA, the rate of non-viral OI was higher among new users of TNFI with autoimmune diseases compared to non-biological DMARD users.

Brief report: incidence of selected opportunistic infections among children with juvenile idiopathic arthritis.

OBJECTIVE: To compare incidence rates of selected opportunistic infections among children with and children without juvenile idiopathic arthritis (JIA). METHODS: Using U.S. national Medicaid administrative claims data from 2000 through 2005, we identified a cohort of children with JIA based on physician diagnosis codes and dispensed medications. We also identified a non-JIA comparator cohort of children diagnosed as having attention deficit hyperactivity disorder (ADHD). We defined 15 types of opportunistic infection using physician diagnosis or hospital discharge codes; criteria for 7 of these types also included evidence of treatment with specific antimicrobial agents. We calculated infection incidence rates. The rates in the ADHD comparator cohort were standardized to the age, sex, and race distribution of the JIA cohort. We calculated incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) to compare infection rates. RESULTS: The JIA cohort included 8,503 children with 13,990 person-years of followup. The ADHD comparator cohort included 360,362 children with 477,050 person-years of followup. When all opportunistic infections were considered together as a single outcome, there were 42 infections in the JIA cohort (incidence rate 300 per 100,000 person-years; IRR 2.4 [95% CI 1.7-3.3] versus ADHD). The most common opportunistic infections among children with JIA were 3 cases of Coccidioides (incidence rate 21 per 100,000 person-years; IRR 101 [95% CI 8.1-5,319] versus ADHD), 5 cases of Salmonella (incidence rate 35 per 100,000 person-years; IRR 3.8 [95% CI 1.2-9.5]), and 32 cases of herpes zoster (incidence rate 225 per 100,000 person-years; IRR 2.1 [95% CI 1.4-3.0]). CONCLUSION: Opportunistic infections are rare among children with JIA. Nevertheless, children with JIA had a higher rate of opportunistic infections, including an increased rate of Coccidioides, Salmonella, and herpes zoster compared to children with ADHD.

Use of health plan combined with registry data to predict clinical trial recruitment.

BACKGROUND: Large pragmatic clinical trials (PCTs) are increasingly used to conduct comparative effectiveness research. In the context of planning a safety PCT of the live herpes zoster vaccine in rheumatoid arthritis (RA) patients aged ≥ 50 years receiving anti-tumor necrosis factor (TNF) therapy, we evaluated the use of health plan combined with registry data to assess the feasibility of recruiting the 4000 patients needed for the trial and to facilitate site selection. METHODS: Using national US data from Medicare, we identified older RA patients who received anti-TNF therapy in the last quarter of 2009. Extrapolations were made from the Medicare patient population to younger patients and those with other types of insurance using the Consortium of Rheumatology Researchers of North America (CORRONA) disease registry. Patients' treating rheumatologists were grouped into practices and sorted by size from the greatest to the least number of eligible patients. RESULTS: Approximately 50,000 RA patients receiving anti-TNF therapy were identified in the Medicare data, distributed across 1980 physician practices. After augmenting Medicare data with information from CORRONA and extrapolating to younger patients and those with other types of insurance, more than 12,000 potentially eligible study subjects were identified from the 50 largest rheumatology practices. CONCLUSION: Health plan and registry databases appear useful to assess feasibility of large pragmatic trials and to assist in selection of recruitment sites with the greatest number of potentially eligible patients. This novel approach is applicable to trials with simple inclusion/exclusion criteria that can be readily assessed in these data sources.

Republished: The association between inflammatory markers, serum lipids and the risk of cardiovascular events in patients with rheumatoid arthritis.

OBJECTIVE: To examine the association of serum inflammatory markers (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) and serum lipid measures (low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol) with risk of myocardial infarction (MI) and ischaemic stroke (IS) among rheumatoid arthritis (RA) patients. METHODS: We conducted a retrospective cohort study using 2005-2010 data from a US commercial health plan. Eligible patients had two or more physician diagnoses of RA during a baseline period of at least 180 days with continuous medical and pharmacy coverage. We computed age-adjusted incidence rates of MI and IS, and used spline regression to assess non-linear associations and Cox-regression to quantify the independent association between the laboratory values and the outcomes. RESULTS: We identified 44 418 eligible RA patients (mean age 49 years; 76% women). CRP>10 mg/L compared with <1 mg/L was associated with increased MI risk (HR 2.12; 95% CI 1.02 to 4.38). ESR>42 mm/h compared with <14 mm/h was associated with increased risk of MI (HR 2.53; 95% CI 1.48 to 4.31) and IS (HR 2.51; 95% CI 1.33 to 4.75) risk. HDL-cholesterol ≥60 mg/dL (1.6 mmol/L) compared with <40 mg/dL (1.0 mmol/L) was associated with reduced MI risk (HR 0.37; 0.21 to 0.66). The association between LDL and MI was not linear; the lowest risk was observed among patients with LDL between 70 mg/L (1.8 mmol/L) and 100 mg/L (2.6 mmol/L). We did not observe a significant association between LDL and IS. CONCLUSIONS: This study provides evidence supporting the hypothesis that RA-related systemic inflammation plays a role in determining cardiovascular risk and a complex relationship between LDL and cardiovascular risk.

Claims-based algorithms for identifying Medicare beneficiaries at high estimated risk for coronary heart disease events: a cross-sectional study.

BACKGROUND: Databases of medical claims can be valuable resources for cardiovascular research, such as comparative effectiveness and pharmacovigilance studies of cardiovascular medications. However, claims data do not include all of the factors used for risk stratification in clinical care. We sought to develop claims-based algorithms to identify individuals at high estimated risk for coronary heart disease (CHD) events, and to identify uncontrolled low-density lipoprotein (LDL) cholesterol among statin users at high risk for CHD events. METHODS: We conducted a cross-sectional analysis of 6,615 participants ≥66 years old using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study baseline visit in 2003-2007 linked to Medicare claims data. Using REGARDS data we defined high risk for CHD events as having a history of CHD, at least 1 risk equivalent, or Framingham CHD risk score >20%. Among statin users at high risk for CHD events we defined uncontrolled LDL cholesterol as LDL cholesterol ≥100 mg/dL. Using Medicare claims-based variables for diagnoses, procedures, and healthcare utilization, we developed algorithms for high CHD event risk and uncontrolled LDL cholesterol. RESULTS: REGARDS data indicated that 49% of participants were at high risk for CHD events. A claims-based algorithm identified high risk for CHD events with a positive predictive value of 87% (95% CI: 85%, 88%), sensitivity of 69% (95% CI: 67%, 70%), and specificity of 90% (95% CI: 89%, 91%). Among statin users at high risk for CHD events, 30% had LDL cholesterol ≥100 mg/dL. A claims-based algorithm identified LDL cholesterol ≥100 mg/dL with a positive predictive value of 43% (95% CI: 38%, 49%), sensitivity of 19% (95% CI: 15%, 22%), and specificity of 89% (95% CI: 86%, 90%). CONCLUSIONS: Although the sensitivity was low, the high positive predictive value of our algorithm for high risk for CHD events supports the use of claims to identify Medicare beneficiaries at high risk for CHD events.