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1.  Use of Health Plan Combined with Registry Data to Predict Clinical Trial Recruitment 
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 age ≥ 50 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 4,000 patients needed for the trial and to facilitate site selection.
Using national United States 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.
Approximately 50,000 RA patients receiving anti-TNF therapy were identified in the Medicare data, distributed across 1,980 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 40-45 largest rheumatology practices.
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.
PMCID: PMC4199104  PMID: 24346611
pragmatic trial; clinical trial; registry; administrative data; recruitment; rheumatoid arthritis; anti-TNF therapy; herpes zoster; shingles
2.  Non-viral Opportunistic Infections in New Users of TNF Inhibitor Therapy: Results of the SAfety Assessment of Biologic ThERapy (SABER) Study 
Annals of the rheumatic diseases  2013;73(11):1942-1948.
To determine among patients with autoimmune diseases in the United States whether the risk of non-viral opportunistic infections (OIs) was increased among new users of tumor necrosis factor-alpha inhibitors (TNFI), when compared to users of non-biologic agents used for active disease.
We identified new users of TNFI among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis-psoriatic arthritis-ankylosing spondylitis (PsO-PsA-AS) patients during 1998–2007 using combined data from Kaiser Permanente Northern California, two pharmaceutical assistance programs for the elderly, Tennessee Medicaid, and US Medicaid/Medicare programs. We compared incidence of non-viral OIs among new TNFI users and patients initiating non-biologic disease modifying drugs (DMARDs) 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-biologic DMARD users.
Within a cohort of 33,324 new TNFI users we identified 80 non-viral OIs, the most common of which was pneumocystosis (n=16). In the combined cohort, crude rates of non-viral OIs among new users of TNFI as compared to those initiating non-biologic DMARDs was 2.7 verus 1.7 per 1000-person years[adjusted hazard ratio (aHR): 1.6, 95% CI: 1.0, 2.6)]. Baseline corticosteroid use was associated with non-viral OIs (aHR 2.5, 95% CI: 1.5, 4.0). In the RA cohort, rates of non-viral OIs among new users of infliximab were higher when compared to patients newly starting non-biologic DMARDs (aHR 2.6, 95% CI 1.2, 5.6) or new etanercept users (aHR 2.9, 95% CI: 1.5, 5.4).
In the US, the rate of non-viral OIs was higher among new users of TNFI with autoimmune diseases as compared to non-biologic DMARD users.
PMCID: PMC4273901  PMID: 23852763
opportunistic infection; tumor necrosis factor-alpha; Pneumocystis; tuberculosis; rheumatoid arthritis
3.  Identifying Newly Approved Medications in Medicare Claims Data: A Case Study Using Tocilizumab 
Pharmacoepidemiology and drug safety  2013;22(11):10.1002/pds.3475.
After U.S. licensure, parenterally administered medications are identified using non-specific drug codes. Accurately identifying these medications is critical to safety and effectiveness research. Methods to identify medications prior to assignment of specific drug codes have not been well described.
To describe a generalized approach using non-specific drug codes to identify parenteral therapies in Medicare claims and to assess the ability of that approach to identify tocilizumab (TCZ), a new biologic agent approved in 2010.
We used 2008–2010 Medicare data for a cohort of rheumatoid arthritis patients for algorithm development. Our algorithm classified non-specific drug codes based upon: (1) ICD9 codes; (2) unit values (i.e. dose); (3) codes for infusion/injection procedures; (4) expected versus observed total reimbursement amount and reimbursement per unit. We assessed algorithm performance by linking to an arthritis registry to examine external validity.
Of 472,803 claims with non-specific drug codes, 9,762 claims satisfied the TCZ algorithm. 74.3% of 9,762 claims were classified as TCZ by exact unit price or allowed amount, 4.4% by unique doses, 21.3% by diagnosis code and small deviation from unit price or allowed amount. The algorithm demonstrated good performance characteristics: sensitivity 94% (95% CI 80–99), specificity 100% (99–100) and PPV 97% (84–100).
Claims-based algorithms in Medicare or similar data systems can accurately identify newly approved biologics administered parenterally prior to the assignment of specific drug codes.
PMCID: PMC3856178  PMID: 24038595
rheumatoid arthritis; Medicare; Part D; biologics; tocilizumab; denosumab; certolizumab; linkage; registry
4.  Incidence of Selected Opportunistic Infections Among Children with Juvenile Idiopathic Arthritis 
Arthritis and rheumatism  2013;65(5):1384-1389.
To compare incidence rates of selected opportunistic infections (OI) among children with and without juvenile idiopathic arthritis (JIA).
Using United States 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 defined a non-JIA comparator cohort of children diagnosed with attention deficit hyperactivity disorder (ADHD). We defined 15 types of OI using physician diagnosis or hospital discharge codes, and 7 of these types also required evidence of treatment with specific antimicrobials. We calculated infection incidence rates (IR). 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 (IRR) to compare infection rates.
The JIA cohort included 8,503 children with 13,990 person-years (p-y) of follow-up. The ADHD comparator cohort included 360,362 children with 477,050 p-y of follow-up. When all OI were considered together as a single outcome, there were 42 infections in the JIA cohort (IR 300 per 100,000 p-y; IRR 2.4 [1.7–3.3] versus ADHD). The most common OI among children with JIA were 3 Coccidioides (IR 21 per 100,000 p-y; IRR 101 [8.1–5319] versus ADHD); 5 Salmonella (IR 35 per 100,000 p-y; IRR 3.8 [1.2–9.5]); and 32 herpes zoster (IR 225 per 100,000 p-y; IRR 2.1 [1.4–3.0]).
OI are rare among children with JIA. Nevertheless, children with JIA had a higher rate of OI, including Coccidioides, Salmonella, and herpes zoster, than children with ADHD.
PMCID: PMC3636167  PMID: 23460423
5.  Use of a Disease Risk Score to Compare Serious Infections Associated with Anti-TNF Therapy among High versus Lower Risk Rheumatoid Arthritis Patients 
Arthritis care & research  2013;65(2):235-243.
To evaluate whether rates of serious infection with anti-TNF therapy in rheumatoid arthritis (RA) patients differ in magnitude by specific drugs and patient characteristics.
Among new non-biologic disease modifying anti-rheumatic drug (DMARD) users enrolled in Medicare/Medicaid or a large U.S. commercial health plan, we created and validated a person-specific infection risk score based upon age, demographics, insurance, glucocorticoid dose, and comorbidities to identify patients at high risk for hospitalized infections. We then applied this risk score to new users of infliximab, etanercept, and adalimumab and compared the observed one-year rate of infection to each other and to the predicted infection risk score estimated in the absence of anti-TNF exposure.
Among 11,657 RA patients initiating anti-TNF therapy, the observed one year rate of infection was 14.2 per 100 person-years in older patients (>= 65 years) and 4.8 in younger patients (< 65 years). There was a relatively constant rate difference of 1–4 infections per 100 person-years associated with anti-TNF therapy across the range of the infection risk score. Infliximab had a significantly greater adjusted rate of infection compared to etanercept and adalimumab in both high and lower risk RA patients.
The rate of serious infections for anti-TNF agents was incrementally increased by a fixed absolute difference irrespective of age, comorbidities, and other factors that contributed to infections. Older patients and those with high comorbidity burdens should be reassured that the magnitude of incremental risk with anti-TNF agents is not greater for them than for lower risk patients.
PMCID: PMC3414685  PMID: 22556118
rheumatoid arthritis; infection; anti-TNF; DMARD; prediction
6.  Association between the initiation of anti-TNF therapy and the risk of herpes zoster 
Herpes zoster (HZ) reactivation disproportionately affects patients with rheumatoid arthritis (RA). It is unclear whether anti-tumor necrosis factor (anti-TNF) therapy elevates HZ risk, and whether monoclonal antibodies carry greater risk than etanercept.
To ascertain whether initiation of anti-TNF therapy compared with non-biologic comparators is associated with increased HZ risk
Design, Setting, and Patients
We identified new users of anti-TNF therapy among cohorts of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis-psoriatic arthritis-ankylosing spondylitis (PsO-PsA-AS) patients during 1998–2007 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 HZ incidence between new anti-TNF users and patients initiating non-biologic disease modifying drugs (DMARDs) within each inflammatory disease cohort (last participant follow-up Dec 31, 2007). Within these cohorts, we used Cox regression models to compare propensity-score adjusted HZ incidence between new anti-TNF and non-biologic DMARD users while controlling for baseline corticosteroid use.
Main Outcome Measure
Incidence of herpes zoster cases occurring after initiation of new anti- TNF or non-biologic DMARD therapy
Among 32,208 new users of anti-TNF therapy, we identified 310 HZ cases. Crude incidence rates among anti-TNF users for RA, IBD, and PsO-PsA-AS were 12.1/1000 pt-yrs, (95% CI 10.7–13.6), 11.3/1000 (95% CI 7.7–16.7), and 4.4/1000 (95% CI 2.8–7.0) respectively. Baseline use of corticosteroids of > 10mg/day was associated with elevated risk [adjusted HR 2.13 (1.64, 2.75) compared with no baseline use. For RA patients, 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 three anti-TNF therapies studied.
Conclusions and Relevance
Among patients with RA and other select inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk for HZ compared to patients who initiated non-biologic treatment regimens.
PMCID: PMC3773213  PMID: 23462785
shingles; zoster; herpes; biologic therapy; tumor necrosis factor-alpha; rheumatoid arthritis; adverse events; psoriasis
7.  Rates of Hospitalized Bacterial Infection Associated with Juvenile Idiopathic Arthritis and Its Treatment 
Arthritis and rheumatism  2012;64(8):2773-2780.
Compare the incidence of hospitalized bacterial infections among children with and without juvenile idiopathic arthritis (JIA) and examine the effects of selected medications
Using national U.S. Medicaid data from 2000–2005, we identified a JIA cohort and a comparator cohort of children with attention-deficit hyperactivity disorder (ADHD). Exposures to methotrexate (MTX), TNF inhibitors, and oral glucocorticoids were determined using pharmacy claims. Hospitalized bacterial infections were identified using coded discharge diagnoses. We calculated adjusted hazard ratios (aHR) to compare infection incidence rates while adjusting for relevant covariates.
We identified 8,479 JIA patients with 13,003 person-years of follow-up; 42% used MTX and 17% used TNF inhibitors. Compared with ADHD patients, JIA patients without current MTX or TNF inhibitor use had an increased rate of infection (aHR 2.0; 95%CI 1.5–2.5). Among JIA patients not using TNF inhibitor therapy, MTX users had a similar rate of infection compared with those without current MTX use (aHR 1.2; 95%CI 0.9–1.7). TNF inhibitor use (irrespective of MTX) resulted in a similar rate of infection compared to MTX without TNF inhibitor (aHR 1.2; 95%CI 0.8–1.8). With adjustment for MTX and TNF inhibitor use, high-dose glucocorticoid use (≥10 mg of prednisone daily) increased the rate of infection compared with no glucocorticoid use (aHR 3.1; 95%CI 2.0–4.7).
Children with JIA had an increased rate of infection compared to children with ADHD. Among children with JIA, the rate of infection was not increased with MTX or TNF inhibitor use, but was significantly increased with high-dose glucocorticoid use.
PMCID: PMC3409300  PMID: 22569881
8.  Association between Vaccination for Herpes Zoster and Risk of Herpes Zoster Infection among Older Patients with Selected Immune-mediated Diseases 
Based on limited data, the live attenuated herpes zoster (HZ) vaccine is contraindicated in patients taking anti-tumor necrosis factor alpha (anti-TNF) therapies or other biologics commonly used to treat immune-mediated diseases. The safety and effectiveness of the vaccine is unclear for these patients.
To examine the association between HZ vaccination and HZ incidence within and beyond 42 days after vaccination in patients with selected immune-mediated diseases and in relation to biologics and other therapies used to treat these conditions.
Design, Setting and Patients
Retrospective cohort study of 463,541 Medicare beneficiaries 60 years and older with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel disease using Medicare claims data from 1/1/2006 to 12/31/2009.
Main Outcome Measure(s)
HZ incidence rate within 42 days after vaccination (a safety concern) and beyond 42 days; hazard ratios estimated using Cox proportional hazards models for HZ comparing vaccinated versus unvaccinated patients.
Median (inter-quartile range) duration of follow-up was 2.0 (0.8-3.0) years; 4.0% of patients received HZ vaccine. The overall crude HZ incidence rate (95% Confidence Interval [CI]) was 7.8 (3.7-16.5) cases per 1,000 person-years (PYs) within 42 days after vaccination. The rate among the unvaccinated was 11.7 cases per 1,000 PYs (95% CI: 11.4-11.9). Among 633 patients exposed to biologics at the time of vaccination or within the subsequent 42 days, no case of HZ or varicella occurred. After multivariable adjustment, HZ vaccination was associated with a hazard ratio of 0.61 (95% CI: 0.52-0.71) for HZ risk after 42 days.
Receipt of HZ vaccine was not associated with a short-term increase in HZ incidence among Medicare beneficiaries with selected immune-mediated diseases, including those exposed to biologics. The vaccine was associated with a lower HZ incidence over a median of 2 years of follow up.
PMCID: PMC3683869  PMID: 22760290
9.  Rates of Malignancy Associated with Juvenile Idiopathic Arthritis and Its Treatment 
Arthritis and Rheumatism  2012;64(4):1263-1271.
To determine relative rates of incident malignancy among children with juvenile idiopathic arthritis (JIA) with respect to treatment compared to children without JIA
Using national U.S. Medicaid data from 2000 through 2005, we identified cohorts of children with JIA and without JIA using physician diagnosis codes and dispensed medication prescriptions. Study follow-up began after a 6 month lag period to exclude prevalent and misdiagnosed malignancies. Treatment with methotrexate and TNF inhibitors was categorized as ever or never exposed. Malignancy outcomes were identified using an adapted version of a previously validated algorithm. Incident malignancies were categorized as possible, probable, or highly probable based on a comprehensive review of all claims. Malignancy rates were standardized to the age, sex, and race distribution of the overall JIA cohort. Standardized incidence ratios (SIR) were calculated using children without JIA (N=321,821) as the referent group.
The JIA cohort included 7,812 children with a total follow-up time of 12,614 person-years, of whom 1,484 children contributed 2,922 person-years of TNF inhibitor exposure. For all children with JIA versus children without JIA, the SIR was 4.4 (1.8–9.0) for probable and highly probable malignancies. For methotrexate users without TNF inhibitor use, the SIR was 3.9 (0.4–14). Following any use of TNF inhibitors, no probable or highly probable malignancies were identified (SIR 0 (0–9.7)).
Children with JIA appeared to have an increased rate of incident malignancy compared to children without JIA. JIA treatment, including TNF inhibitors, did not appear significantly associated with the development of malignancy.
PMCID: PMC3315602  PMID: 22328538
10.  FAS mRNA editing in human Systemic Lupus Erythematosus 
Human mutation  2011;32(11):1268-1277.
FAS/FASL system plays a central role in maintaining peripheral immune tolerance. Human SLE is a prototypic systemic autoimmune disease characterized by expansion of autoreactive lymphocytes. It remains unclear whether a defective FAS/FASL system is involved in the pathogenesis of SLE. In this study, we have discovered a novel nucleotide insertion in FAS mRNA. We demonstrate that this novel FAS mutation occurs at mRNA levels, likely through a site-specific mRNA editing process. The mRNA editing mutation is unique for human FAS because the similar mRNA editing event is absent in other human TNFR family genes with death domains (DR5, DR6, and TNFR1) and in murine FAS. The adenine insertion mutation in the coding region message causes the alteration of human FAS mRNA reading frame. Functionally, cells expressing the edited FAS (edFAS) were refractory to FAS-mediated apoptosis. Surprisingly, cells from SLE patients produced significantly more edFAS products compared to cells from normal healthy controls. Additionally, we demonstrated that persistent engagement of T cell receptor increases human FAS mRNA editing in human T cells. Our data suggest that the site-specific FAS mRNA editing mutation may play a critical role in human immune responses and in the pathogenesis of human chronic inflammatory diseases.
PMCID: PMC3196739  PMID: 21793106
FAS; mRNA editing; apoptosis; Systemic Lupus Erythematosus
11.  Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases 
Although tumor necrosis factor alpha (TNF-α) antagonists are increasingly used in place of non-biologic comparator medications, their safety profile remains incomplete.
To determine whether initiation of TNF-α antagonists compared with non-biologic comparators is associated with an increased risk of serious infections.
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 (PsO-PsA-AS) combining data from Kaiser Permanente Northern California, New Jersey and Pennsylvania Pharmaceutical Assistance programs, Tennessee Medicaid and National Medicaid/Medicare. TNF-α antagonists and non-biologic regimens were compared in disease specific-propensity score (PS) matched cohorts using Cox regression models with non-biologics as 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 non-biologic regimens.
Study cohorts included 10484 RA, 2323 IBD and 3213 PsO-PsA-AS PS-matched pairs using TNF-α antagonists and comparator medications. Overall, we identified 1171 serious infections, most of which (53%) were pneumonia and skin and soft tissue infections. Among RA patients, serious infection hospitalization rates were 8.16 (TNF-α antagonists) and 7.78 (comparator regimens) per 100 person-years (adjusted hazard ratio [aHR]: 1.07 (95% CI: 0.93–1.23)). Among IBD patients, rates were 10.91 and 9.60 per 100 person-years (aHR: 1.13, (0.85–1.50)). Among PsO-PsA-AS patients, rates were 5.41 and 5.19 per 100 person-years (aHR: 1.10, (0.80–1.53)). Among RA patients, infliximab was associated with a significant increase in serious infections compared with etanercept and adalimumab (aHRs: 1.27 (1.08–1.49) and 1.23 (1.02–1.48)). Baseline glucocorticoid use was associated with a dose-dependent increase in infections.
Among patients with autoimmune diseases, compared to treatment with non-biologic regimens, initiation of TNF-α antagonists was not associated with an increased risk of hospitalizations for serious infections.
PMCID: PMC3428224  PMID: 22056398
Rheumatoid arthritis; inflammatory bowel disease; psoriasis; psoriatic arthritis; ankylosing spondylitis; infliximab; etanercept; adalimumab; safety; infection
12.  The Incidence of Gastrointestinal Perforations Among Rheumatoid Arthritis Patients 
Arthritis and rheumatism  2011;63(2):346-351.
Gastrointestinal (GI) perforation has emerged as a novel safety concern in relation to medications used for rheumatoid arthritis (RA). However, the incidence and risk factors for GI perforation have not been well characterized in RA patients.
Using administrative databases of a large U.S. health plan, we identified RA patients treated with biologics, methotrexate, oral glucocorticoids, and NSAIDs; additional risk factors were evaluated including diverticulitis. Hospitalized GI perforation was identified using a validated algorithm. Incidence rates and risk factors were evaluated using Cox proportional hazards models.
Among 40,841 RA patients, 37 hospitalizations with GI perforation were identified. The rate of GI perforation among current biologic users concomitantly exposed to oral glucocorticoids was higher (rate=1.12 per 1,000 patient-years [py], 95% CI 0.50, 2.49) than for biologic users who were not glucocorticoid users (rate=0.47 per 1000py, 95% CI 0.22, 0.98) or MTX users using glucocorticoids (rate=0.87 per 1000py, 95% CI 0.36, 2.10). Neither biologics nor MTX were significantly associated with perforation, in contrast to current use of glucocorticoids and NSAIDs together (hazard ratio =4.7, 95% CI 1.9, 12.0) or glucocorticoids alone (hazard ratio=2.8, 95% CI 1.3, 6.1). Diverticulitis also was a strong risk factor (hazard ratio = 9.1, 95% CI 3.1, 26.4). Seventy percent of perforation cases used glucocorticoids, had antecedent diverticulitis, or both.
GI perforationis an uncommon but serious adverse event among RA patients. Because a majority of patients were either glucocorticoid users or had previously-recognized diverticulitis, these individuals should be considered at higher risk.
PMCID: PMC3031757  PMID: 20967860
rheumatoid arthritis; tumor necrosis factor antagonist; gastrointestinal perforation; methotrexate; glucocorticoids; NSAIDs
13.  The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study 
Arthritis Research & Therapy  2011;13(5):R174.
Zostavax, a live attenuated vaccine, has been approved in the United States for use in older individuals to reduce the risk and severity of herpes zoster (HZ), also known as shingles. The vaccine is contraindicated in individuals taking anti-tumor necrosis factor alpha (anti-TNF) therapies or other biologics commonly used to treat autoimmune diseases because of the safety concern that zoster vaccine may be associated with a short-term HZ risk. The objective of the study was to examine the use, safety (short-term HZ risk after vaccination), and effectiveness of zoster vaccine in individuals with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel diseases.
We conducted a cohort study of patients aged 50 years and older with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and/or inflammatory bowel diseases by using administrative claims data from a nationwide health plan from January 1, 2005, to August 31, 2009. We examined the extent to which zoster vaccine was used; assessed factors associated with vaccine use (Cox proportional hazards regression); and compared the incidence rates of herpes zoster (HZ) between vaccinated and unvaccinated patients.
Among 44,115 patients with the autoimmune diseases, 551 (1.2%) received zoster vaccine, and 761 developed HZ. Zoster vaccine use increased continuously after approval in 2006. Younger and healthier patients, those who had an HZ infection within the past 6 months, and those who were not using anti-TNF therapies were more likely to receive the vaccine. Approximately 6% of vaccinated patients were using anti-TNF therapies at the time of vaccination. The incidence rates of HZ were similar in vaccinated and unvaccinated patients (standardized incidence ratio, 0.99; 95% confidence interval, 0.29 to 3.43).
Use of the zoster vaccine was uncommon among older patients with autoimmune diseases, including those not exposed to immunosuppressive medications. The short-term risk of HZ did not appear to be increased in vaccinated patients, even among those using immunosuppressive therapies (for example, biologics) at the time of vaccination. However, our study was limited by the small number of vaccinated patients, and further evidence is needed to confirm the vaccine's safety and efficacy in this population.
PMCID: PMC3308109  PMID: 22024532
14.  Human FasL Gene Is a Target of β-Catenin/T-Cell Factor Pathway and Complex FasL Haplotypes Alter Promoter Functions 
PLoS ONE  2011;6(10):e26143.
FasL expression on human immune cells and cancer cells plays important roles in immune homeostasis and in cancer development. Our previous study suggests that polymorphisms in the FasL promoter can significantly affect the gene expression in human cells. In addition to the functional FasL SNP -844C>T (rs763110), three other SNPs (SNP -756A>G or rs2021837, SNP -478A>T or rs41309790, and SNP -205 C>G or rs74124371) exist in the proximal FasL promoter. In the current study, we established three major FasL hyplotypes in humans. Interestingly, a transcription motif search revealed that the FasL promoter possessed two consensus T-cell factor (TCF/LEF1) binding elements (TBEs), which is either polymorphic (SNP -205C>G) or close to the functional SNP -844C>T. Subsequently, we demonstrate that both FasL TBEs formed complexes with the TCF-4 and β-catenin transcription factors in vitro and in vivo. Co-transfection of LEF-1 and β-catenin transcription factors significantly increased FasL promoter activities, suggesting that FasL is a target gene of the β-catenin/T-cell factor pathway. More importantly, we found that the rare allele (-205G) of the polymorphic FasL TBE (SNP -205C>G) failed to bind the TCF-4 transcription factor and that SNP -205 C>G significantly affected the promoter activity. Furthermore, promoter reporter assays revealed that FasL SNP haplotypes influenced promoter activities in human colon cancer cells and in human T cells. Finally, β-catenin knockdown significantly decreased the FasL expression in human SW480 colon cancer cells. Collectively, our data suggest that β-catenin may be involved in FasL gene regulation and that FasL expression is influenced by FasL SNP haplotypes, which may have significant implications in immune response and tumorigenesis.
PMCID: PMC3191176  PMID: 22022540
15.  Geographic Distribution of Endemic Fungal Infections among Older Persons, United States1 
Emerging Infectious Diseases  2011;17(9):1664-1669.
TOC summary: Incidence was highest for histoplasmosis and blastomycosis in the Midwest and for coccidioidomycosis in the West.
To investigate the epidemiology and geographic distribution of histoplasmosis, coccidioidomycosis, and blastomycosis in older persons in the United States, we evaluated a random 5% sample of national Medicare data from 1999 through 2008. We calculated national, regional, and state-based incidence rates and determined 90-day postdiagnosis mortality rates. We identified 776 cases (357 histoplasmosis, 345 coccidioidomycosis, 74 blastomycosis). Patient mean age was 75.7 years; 55% were male. Histoplasmosis and blastomycosis incidence was highest in the Midwest (6.1 and 1.0 cases/100,000 person-years, respectively); coccidioidomycosis incidence rate was highest in the West (15.2). On the basis of available data, for 86 (11.1%) cases, there was no patient exposure to a traditional disease-endemic area. Knowledge of areas where endemic mycosis incidence is increased may affect diagnostic or prevention measures for older adults at risk.
PMCID: PMC3322071  PMID: 21888792
endemic mycoses; histoplasmosis; coccidioidomycosis; blastomycosis; rheumatoid arthritis; fungi; geographic distribution; United States; dispatch
16.  The comparative risk of serious infections among rheumatoid arthritis patients starting or switching biological agents 
Annals of the rheumatic diseases  2011;70(8):1401-1406.
It is unclear whether anti-tumour necrosis factor alpha and biological agents with different mechanisms of action have similar safety. This study evaluated the incidence of hospitalised infections among rheumatoid arthritis (RA) patients starting or switching various biological agents.
Using a database from a large US healthcare organisation from January 2005 to August 2009, the authors identified enrollees with RA and their treatment episodes entailing the new use of a biological agent, stratified by no biological use in the previous year (‘biological-free’) or switching from a different biological agent (‘switchers’). Outcomes were hospitalised infections identified using previously validated algorithms. Proportional hazards models estimated the hazard ratio of hospitalised infections, comparing each biological agent with infliximab.
Among 7847 biological treatment episodes, 63% were for biological-free patients and 37% for switchers. There were 364 hospitalised infections. Rates of hospitalised infection among biological-free patients and switchers were 4.6 and 7.0 per 100 person-years, respectively (p<0.0001). After multivariable adjustment controlling for biological-free/switcher status and other infection-related factors and compared with infliximab, users of abatacept (HR 0.68, 95% CI 0.48 to 0.96), adalimumab (HR 0.52, 0.39 to 0.71), etanercept (HR 0.64, 0.49 to 0.84) and rituximab (HR 0.81, 0.55 to 1.20) had lower rates of hospitalised infection. Patient risk factors contributed more to the risk of infection than did the risk associated with specific biological therapies.
The rate of hospitalised infections among RA patients was highest for infliximab. Most of the variability in patients’ risk of infection was driven by factors other than biological agent exposure.
PMCID: PMC3128235  PMID: 21586439

Results 1-16 (16)