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1.  Regional differences regarding risk of developing Rheumatoid Arthritis in Stockholm County, Sweden 
Scandinavian journal of rheumatology  2013;42(5):10.3109/03009742.2013.769062.
Objectives
Rheumatoid arthritis (RA) is a complex disease that is associated with genetic and environmental factors. We have investigated geospatial variation in risk of developing RA within Stockholm County, with respect to established environmental risk factors for RA, as well as serologically-defined subgroups of RA.
Methods
Information regarding geographical location for 1432 cases and 2529 controls from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, living in Stockholm County at RA symptom onset, or matched date for controls, was used to estimate geospatial variation in risk. We used Generalized Additive Models (GAM) to create a risk surface, calculate odds ratios and adjust for potential confounding by smoking, educational level and RA within family. We performed a stratified analysis based on presence/absence of antibodies to citrullinated peptides (ACPA).
Results
We found significant spatial variation in the odds of developing RA in Stockholm County. After adjustment for smoking, educational level and family history of RA, this geospatial variation remained. The stratified analysis showed areas with higher odds ratios for ACPA-positive RA and ACPA-negative RA, after adjusting for smoking, educational level and having a family history of RA. Living in the city of Stockholm was associated with decreased risk of RA.
Conclusion
The risk of developing RA in Stockholm County is not evenly distributed and there are areas of increased risk that could not be explained by known factors. Further investigations of local exposures or social factors are warranted.
doi:10.3109/03009742.2013.769062
PMCID: PMC3815679  PMID: 23611369
Rheumatoid Arthritis; Epidemiologic methods; Antibodies; Geography; Risk; Smoking; ACPA; Stockholm
2.  Lymphoma risk in systemic lupus: effects of disease activity versus treatment 
Annals of the rheumatic diseases  2013;73(1):10.1136/annrheumdis-2012-202099.
Objective
To examine disease activity versus treatment as lymphoma risk factors in systemic lupus erythematosus (SLE).
Methods
We performed case–cohort analyses within a multisite SLE cohort. Cancers were ascertained by regional registry linkages. Adjusted HRs for lymphoma were generated in regression models, for time-dependent exposures to immunomodulators (cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarial drugs, glucocorticoids) demographics, calendar year, Sjogren’s syndrome, SLE duration and disease activity. We used adjusted mean SLE Disease Activity Index scores (SLEDAI-2K) over time, and drugs were treated both categorically (ever/never) and as estimated cumulative doses.
Results
We studied 75 patients with lymphoma (72 non-Hodgkin, three Hodgkin) and 4961 cancer-free controls. Most lymphomas were of B-cell origin. As is seen in the general population, lymphoma risk in SLE was higher in male than female patients and increased with age. Lymphomas occurred a mean of 12.4 years (median 10.9) after SLE diagnosis. Unadjusted and adjusted analyses failed to show a clear association of disease activity with lymphoma risk. There was a suggestion of greater exposure to cyclophosphamide and to higher cumulative steroids in lymphoma cases than the cancer-free controls.
Conclusions
In this large SLE sample, there was a suggestion of higher lymphoma risk with exposure to cyclophosphamide and high cumulative steroids. Disease activity itself was not clearly associated with lymphoma risk. Further work will focus on genetic profiles that might interact with medication exposure to influence lymphoma risk in SLE.
doi:10.1136/annrheumdis-2012-202099
PMCID: PMC3855611  PMID: 23303389
3.  Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci 
Nature genetics  2010;42(6):508-514.
To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles.
doi:10.1038/ng.582
PMCID: PMC4243840  PMID: 20453842
4.  SEX-SPECIFIC ENVIRONMENTAL INFLUENCES ON THE DEVELOPMENT OF AUTOIMMUNE DISEASES 
Clinical immunology (Orlando, Fla.)  2013;149(2):182-191.
Sex differences in autoimmune diseases are evolutionarily tied to the fact that the female immune system is confronted with intense alterations during menstrual cycles, pregnancy and childbirth. These events may be associated with breaches in the mucosal epithelial layers that are shielding us from environmental factors. Associations between environmental agents and autoimmune diseases have been described extensively in prior studies. Little evidence, however, exists for sex-specific environmental effects on autoimmune diseases. In this review, we summarize studies involving this often-neglected aspect. We give examples of environmental factors that may influence the sex bias in autoimmunity. We conclude that most studies do not give insight into sex-specific environmental effects due to the influence of gender-selective social, occupational or other exposures. Prospective studies are needed in order to determine true sex-biased environmental influences. Finally, humanized murine models might aid in better understanding the mechanisms involved in sex-specific environmental effects on autoimmune diseases.
doi:10.1016/j.clim.2013.02.011
PMCID: PMC3805711  PMID: 23507400
autoimmunity; chemicals; smoking; infectious agents; commensal bacteria; microbiota
5.  Epstein-Barr Virus Serologic Abnormalities and risk of Rheumatoid Arthritis among Women 
Autoimmunity  2011;45(2):161-168.
Background
EBV infection and the immune response may be involved in the pathogenesis of rheumatoid arthritis (RA). Past studies have suggested an association between EBV and RA.
Methods
We studied the association between EBV serologies and RA risk in a nested case-control study in the Nurses’ Health Study cohorts. We confirmed incident RA cases from 1990–2002 by questionnaire and medical record review. Each incident case with blood collected prior to RA symptoms was matched to a healthy participant by time of day and date of blood collection, birth year, menopausal status and postmenopausal hormone use. Immunofluorescence assays measured serologic EBV responses: viral capsid antigen (VCA), early-antigen-diffuse (EA-D) and early antigen-complex (EA-restricted and diffuse), Epstein Barr nuclear antigen (EBNA)-1, EBNA-2 and cytomegalovirus (CMV), as control. All were reported as titers, except BZLF-1 and CMV, which were reported as positive or negative. ANA positive samples were excluded. Elevated EBV antibody titers were defined as the upper 20% (or nearest titer) among controls. Conditional logistic regression analyses modeled RA risk associated with elevated EBV titers or the presence/absence CMV, further adjusted for pack-years smoking and alcohol intake.
Results
87 incident RA cases were identified. Mean time to RA after blood draw was 6.2 (±3.5) years in NHS and 1.9 (±0.6) years in NHSII. Antibody titers against EBV were not significantly different between pre-RA cases and controls.
Conclusions
In this prospective study of women, we observed no association between EBV serologies and RA risk.
doi:10.3109/08916934.2011.616557
PMCID: PMC3548398  PMID: 22011088
rheumatoid arthritis; Epstein Barr virus; virus; risk factors; epidemiology
6.  Variation in Initial Kidney Replacement Therapy for End-Stage Renal Disease Due to Lupus Nephritis in the U.S. 
Arthritis care & research  2011;63(12):1642-1653.
Objective
Little is known about patterns of use of initial kidney replacement therapies among patients with LN end-stage renal disease (LN ESRD). We aimed to identify sociodemographic and clinical factors associated with variation in initial kidney replacement therapies among LN ESRD patients.
Methods
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Data System. Age, sex, race, ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered as potential predictors of ESRD treatment choice -- peritoneal dialysis (PD), hemodialysis (HD) or pre-emptive kidney transplantation -- in age-adjusted and multivariable-adjusted logistic regression analyses.
Results
Of 11,317 individuals with incident LN ESRD, 82.0% initiated HD; 12.2% PD, and 2.8% underwent pre-emptive kidney transplantation. Receiving initial PD was significantly associated with earlier calendar year, female sex, higher albumin and hemoglobin, and lower serum creatinine levels. African Americans (vs. Whites), Medicaid beneficiaries and those with no health insurance (vs. private insurance), and those unemployed (vs. employed) had significantly reduced PD initiation. Comorbidities including congestive heart failure, peripheral vascular disease and inability to ambulate were also associated with decreased PD. Many sociodemographic and clinical factors favoring PD were associated with pre-emptive kidney transplant (vs. dialysis) as well.
Conclusion
Few patients with LN ESRD receive initial PD or pre-emptive kidney transplantation. Race, ethnicity, employment and medical insurance type are strongly associated with initial kidney replacement therapy choice. Future studies need to investigate the appropriateness of sociodemographic and clinical variation and the comparative effectiveness of kidney replacement therapies for LN ESRD.
doi:10.1002/acr.20607
PMCID: PMC3227771  PMID: 22058067
peritoneal dialysis; hemodialysis; kidney transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
7.  The Association between Silica Exposure and Development of ANCA-Associated Vasculitis: Systematic Review and Meta-analysis 
Autoimmunity reviews  2013;12(12):1129-1135.
Background
Crystalline silica is among the environmental exposures associated with increased risk of autoimmune diseases, including rheumatoid arthritis, systemic sclerosis and systemic lupus erythematosus. Silica exposure has also been related to the development of ANCA-associated vasculitides (AAV), but past studies appear to conflict as to the presence and magnitude of the associated risks of disease. We aimed to conduct a systematic review of the existing studies and meta-analysis of their results.
Methods
We searched EMBASE, MEDLINE and international scientific conference abstract databases for studies examining the association of silica exposure with AAV. Studies in English, French, or Spanish were included and those examining the association of silica with ANCA-positivity alone were excluded. We assessed study quality using the Newcastle-Ottawa scale. We meta-analyzed the results using random effects models and tested for heterogeneity. We performed sensitivity and subgroup analyses, examining studies that adjusted for smoking and occupational risk factors as well as studies that analyzed by subtypes of AAV.
Results
We identified 158 potential manuscripts and 3 abstracts related to silica exposure and risk of AAV. 147 were excluded after abstract review and 14 underwent detailed evaluation of full manuscript/abstract. After further application of exclusion criteria, 6 studies (all case-controls) remained. The studies had moderate heterogeneity in selection of cases and controls, exposure assessment, disease definition and controlling for potential confounders. We found an overall significant summary effect estimate of silica “ever exposure” with development of AAV (summary OR 2.56, 95% CI 1.51- 4.36), with moderate heterogeneity (I2=48.40%). ORs were similar for studies examining only MPA (OR 3.95, CI 95% 1.89-8.24), compared to those only studying GPA (OR 3.56, CI 95% 1.85-6.82).
Conclusion
Despite moderate heterogeneity among studies, the totality of the evidence after meta-analysis points to an association between silica exposure and risk for developing AAV.
doi:10.1016/j.autrev.2013.06.016
PMCID: PMC4086751  PMID: 23820041
Antineutrophil cytoplasmic antibodies; ANCA-associated vasculitides; Silica; Meta-analysis
12.  Immunosenescence and Rheumatoid Arthritis: Does Telomere Shortening Predict Impending Disease? 
Autoimmunity reviews  2011;10(9):569-573.
The pathogenesis of RA, a disabling autoimmune disease, is incompletely understood. Early in the development of RA there appears to be loss of immune homeostasis and regulation, and premature immunosenescence. While identification of risk factors and understanding of the phases of RA pathogenesis are advancing, means of accurately predicting an individual’s risk of developing RA are currently lacking. Telomere length has been proposed as a potential new biomarker for the development of RA that could enhance prediction of this serious disease. Studies examining telomere length in relation to RA have found that telomere erosion appears to proceed more rapidly in subjects with RA than in healthy controls, and that telomere lengths are shorter in those with the RA-risk HLA-shared epitope genes. These studies have been small, however, with retrospective or cross-sectional designs. The potential role of telomere shortening as an independent biomarker for future RA risk, perhaps strongly genetically determined by HLA-SE genes, after controlling for known risk factors such as smoking, body mass index and immunosuppressant medication use, as well as systemic inflammation, is an unanswered question.
doi:10.1016/j.autrev.2011.04.034
PMCID: PMC3119949  PMID: 21575746
immunosenescence; rheumatoid arthritis; telomere; biomarker; risk factor; aging; autoimmune
13.  Does Vitamin D Affect Risk of Developing Autoimmune Disease?: A Systematic Review 
Seminars in arthritis and rheumatism  2010;40(6):512-531.e8.
Objectives
We evaluated the epidemiologic evidence that vitamin D may be related to human autoimmune disease risk.
Methods
PubMed limited to English from inception through April 2010 was searched using keywords: “vitamin D”, “autoimmune” and autoimmune disease names. We summarized in vitro, animal, and genetic association studies of vitamin D in autoimmune disease pathogenesis. We sorted studies by design and disease and performed a systematic review of: a) cross-sectional data concerning vitamin D level and autoimmune disease; b) interventional data on vitamin D supplementation in autoimmune diseases and c) prospective data linking vitamin D level or intake to autoimmune disease risk.
Results
Vitamin D has effects on innate and acquired immune systems and vitamin D receptor polymorphisms have been associated with various autoimmune diseases. In experimental animal models, vitamin D supplementation can prevent or forestall autoimmune disease. We identified 76 studies in which vitamin D levels were studied in autoimmune disease patients, particularly with active disease, and compared to controls. Nineteen observational or interventional studies assessed the effect of vitamin D supplementation as therapy for various autoimmune diseases (excluding psoriasis and vitiligo) with a range of study approaches and results. The few prospective human studies performed conflict as to whether vitamin D level or intake is associated with autoimmune disease risk. No interventional trials have investigated whether vitamin D affects human autoimmune disease risk.
Conclusions
Cross-sectional data point to a potential role of vitamin D in autoimmune disease prevention, but prospective interventional evidence in humans is still lacking.
doi:10.1016/j.semarthrit.2010.07.009
PMCID: PMC3098920  PMID: 21047669
vitamin D; autoimmune disease; intake; risk factor; epidemiology; systematic review
14.  Trends in the Incidence, Demographics and Outcomes of End-Stage Renal Disease Due to Lupus Nephritis in the U.S., 1995–2006 
Arthritis and rheumatism  2011;63(6):1681-1688.
Background
It is unknown whether recent advances lupus nephritis (LN) treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to LN, or in the characteristics, therapies, and outcomes of patients with LN ESRD.
Methods
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Datasystem. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses.
Results
12,344 incident cases of LN ESRD were identified. Mean age at ESRD onset was 41 years; 81.6% were female and 49.5% African American. SIRs for LN ESRD among those ages 5–39, African Americans, and in the US Southeast increased significantly from 1995–2006. Increases in body mass index and the prevalence of both diabetes and hypertension were detected. Mean serum hemoglobin at ESRD onset increased, while that of serum creatinine decreased over time. More patients used hemodialysis and fewer peritoneal dialysis. There was a slight increase in pre-emptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first three years of ESRD declined. Mortality did not change over 12 years of study.
Conclusions
The characteristics of LN ESRD patients and their initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans and in the South, outcomes did not improve in over a decade of evaluation.
doi:10.1002/art.30293
PMCID: PMC3106117  PMID: 21445962
incidence; dialysis; transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
15.  Quality of Care for Incident Lupus Nephritis Among Medicaid Beneficiaries in the United States 
Arthritis care & research  2014;66(4):617-624.
OBJECTIVE
We investigated the quality of care and factors associated with variations in care among a national cohort of Medicaid enrollees with incident lupus nephritis.
METHODS
Using Medicaid Analytic eXtract (MAX) files from 47 U.S. states and D.C. for 2000–2006, we identified a cohort of individuals with incident lupus nephritis. We assessed performance on three measures of health care quality: receipt of immunosuppressive, renal-protective anti-hypertensive, and anti-malarial medications. We examined performance on these measures over one year, and applied multivariable logistic regression models to understand whether sociodemographic, geographic or health care access factors were associated with higher performance on quality measures.
RESULTS
We identified 1711 Medicaid enrollees with incident lupus nephritis. Performance on quality measures was low at 90 days (21.9% for immunosuppressive therapy, 44.0% for renal protection and 36.4% for anti-malarials), but increased by one year (33.7%, 56.4%, and 45.8%, respectively). Younger individuals, Blacks and Hispanics were more likely to receive immunosuppressive therapy and hydroxychloroquine. Younger individuals were less likely to receive renal-protective anti-hypertensive medications. We found significant geographic variation in performance, with patients in the Northeast receiving higher quality of care compared to other regions. Poor access to health care, as assessed by having a greater number of treat-and-release emergency departments visits compared to ambulatory encounters, was associated with lower receipt of recommended treatment.
CONCLUSION
These nationwide data suggest low overall quality of care and potential delays in care for Medicaid enrollees with incident lupus nephritis. Significant regional differences also suggest room for quality improvement.
doi:10.1002/acr.22182
PMCID: PMC4109800  PMID: 24124011
16.  Osteoporosis and Cardiovascular Disease Care in SLE According to New Quality Indicators 
Objectives
Quality indicators (QIs) for assessment of care of patients with systemic lupus erythematosus SLE) have been proposed. We evaluated care according to these proposed QIs for osteoporosis and cardiovascular disease (CVD) in patients with SLE in our rheumatology practice.
Methods
We selected 200 patients with SLE according to American College of Rheumatology (ACR) Criteria and ≥ 2 visits to our practice in 2007–8. We performed a structured medical record review and collected demographics, SLE and past medical history, medications, laboratories and data concerning osteoporosis and CVD management. We employed univariable analyses and multivariable regression analyses to test for factors associated with care meeting the proposed QIs.
Results
94% of patients were female and 64% white. Mean age was 46.3 years and mean lupus duration was 15.3 years. 29% were taking ≥ 7.5 mg prednisone per day for ≥ 3 months. The proportions of patients for whom care met the proposed QIs were: 57% for bone mineral density (BMD) testing, 62% for calcium and vitamin D supplementation, and 86% for anti-resorptive or anabolic osteoporosis medications. Only 3% had 5 cardiac risk factors assessed within the year and 26% had 4 cardiac risk factors assessed annually. Smoking, fasting lipid panels and diabetes mellitus were rarely assessed annually. Having a primary care physician (PCP) within our healthcare network increased care meeting QIs.
Conclusions
Care according to newly proposed QIs for osteoporosis and CVD was suboptimal in our academic center. In order to standardize and improve care of patients with SLE, we suggest specific changes to the proposed QIs.
doi:10.1016/j.semarthrit.2010.01.001
PMCID: PMC2932869  PMID: 20378155
systemic lupus erythematosus; quality indicator; osteoporosis; cardiovascular disease; bone mineral density; screening; cholesterol; blood pressure; management; risk factor; calcium and vitamin D
17.  Ambient air pollution exposures and risk of rheumatoid arthritis in the Nurses’ Health Study 
Arthritis care & research  2013;65(7):1190-1196.
Objective
Environmental factors may play a role in the development of rheumatoid arthritis (RA), and we have previously observed increased RA risk among women living closer to major roads (a source of air pollution). We examined whether long-term exposures to specific air pollutants were associated with RA risk among women in the Nurses’ Health Study.
Methods
The Nurses’ Health Study (NHS) is a large cohort of U.S. female nurses followed prospectively every two years since 1976. We studied 111,425 NHS participants with information on air pollution exposures as well as data concerning other lifestyle and behavioral exposures and disease outcomes. Outdoor levels of different size fractions of particulate matter (PM10 and PM2.5) and gaseous pollutants (SO2 and NO2) were predicted for all available residential addresses using monitoring data from the USEPA. We examined the association of time-varying exposures, 6 and 10 years before each questionnaire cycle, and cumulative average exposure with the risks of RA, seronegative (rheumatoid factor [RF] and anti–citrullinated peptide antibodies [ACPA]) RA, and seropositive RA.
Results
Over the 3,019,424 years of follow-up, 858 incident RA cases were validated by medical record review by two board-certified rheumatologists. Overall, we found no evidence of increased risks of RA, seronegative or seropositive RA, with exposure to the different pollutants, and little evidence of effect modification by socioeconomic status or smoking status, geographic region, or calendar period.
Conclusion
In this group of socioeconomically-advantaged middle-aged and elderly women, adult exposures to air pollution were not associated with an increased RA risk.
doi:10.1002/acr.21975
PMCID: PMC3659202  PMID: 23401426
18.  Association of Discoid Lupus with other Clinical Manifestations among Patients with Systemic Lupus Erythematosus 
Background
Cutaneous discoid lupus (DLE) among SLE patients may be associated with less severe disease, with low frequency of nephritis and end-stage renal disease (ESRD).
Objective
To investigate associations between confirmed DLE and other SLE manifestations, adjusting for confounders.
Methods
We identified patients with rheumatologist confirmation, according to ACR SLE classification criteria 1997, >2 visits, >3 months of follow-up, and documented year of SLE diagnosis. DLE was confirmed by dermatologist, supported by histopathology and images. SLE manifestations, medications and serologies were collected. Multivariable-adjusted logistic regression analyses tested for associations between DLE and each of the ACR SLE criteria, and ESRD.
Results
A total of 1,043 SLE patients, (117 with DLE and 926 without DLE), were included in the study. After multivariable adjustment, DLE in SLE was significantly associated with photosensitivity (OR 1.63), leukopenia (OR 1.55) and anti-Smith antibodies (OR 2.41). DLE was significantly associated with reduced risks of arthritis (OR 0.49) and pleuritis (OR 0.56). We found no significant associations between DLE and nephritis or ESRD.
Limitations
Cross-sectional data collection with risk of data not captured from visits outside system.
Conclusions
In our SLE cohort, DLE was confirmed by a dermatologist and we adjusted for possible confounding by medication use, in particular hydroxychloroquine. We found increased risks of photosensitivity, leukopenia and anti-Smith antibodies and decreased risks of pleuritis and arthritis in SLE patients with DLE. DLE was not related to anti-dsDNA antibodies, lupus nephritis, or ESRD. These findings have implications for prognosis among SLE patients.
doi:10.1016/j.jaad.2013.02.010
PMCID: PMC3686921  PMID: 23541758
Systemic lupus erythematosus; discoid lupus erythematosus; cutaneous lupus erythematosus; prognosis; epidemiology
19.  Association of Environmental and Genetic Factors and Gene-Environment Interactions with Risk of Developing Rheumatoid Arthritis 
Arthritis care & research  2013;65(7):1147-1156.
Background
We developed RA risk models based on validated environmental factors (E), genetic risk scores (GRS), and gene-environment interactions (GEI) to identify factors that can improve accuracy and reclassification.
Methods
Models including E, GRS, GEI were developed among 317 Caucasian seropositive RA cases and 551 controls from Nurses’ Health Studies (NHS) and validated in 987 Caucasian ACPA positive cases and 958 controls from the Swedish Epidemiologic Investigation of RA (EIRA), stratified by gender. Primary analyses included age, smoking, alcohol, parity, weighted GRS using 31 non-HLA alleles, 8 HLA-DRB1 alleles and HLA X smoking interaction. Expanded models included reproductive, geographic, and occupational factors, and additional GEI terms. Hierarchical models were compared for discriminative accuracy using AUC and reclassification using Integrated Discrimination Improvement (IDI) and continuous Net Reclassification Index.
Results
Mean (SD) age of RA diagnosis was 57 in NHS and 50 in EIRA. Primary models produced an AUC of 0.716 in NHS, 0.728 in EIRA women and 0.756 in EIRA men. Expanded models produced improvements in discrimination with AUCs of 0.738 in NHS, 0.728 in EIRA women and 0.769 in EIRA men. Models including G or G + GEI improved reclassification over E models; the full E+G+GEI model provided the optimal predictive ability by IDI analyses.
Conclusions
We have developed comprehensive RA risk models incorporating epidemiologic and genetic factors and gene-environment interactions that have improved discriminative accuracy for RA. Further work developing and assessing highly specific prediction models in prospective cohorts is still needed to inform primary RA prevention trials.
doi:10.1002/acr.22005
PMCID: PMC3740546  PMID: 23495093
20.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
Objective
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Methods
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
Results
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
Conclusion
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
doi:10.1002/art.27580
PMCID: PMC3077961  PMID: 20872596
21.  Antioxidant Intake and Risks of Rheumatoid Arthritis and Systemic Lupus Erythematosus in Women 
American Journal of Epidemiology  2010;172(2):205-216.
Antioxidants may protect against development of rheumatoid arthritis or systemic lupus erythematosus by combating oxidative stress. The authors identified and confirmed incident cases of rheumatoid arthritis and systemic lupus erythematosus among 184,643 US women followed in the Nurses’ Health Study and Nurses’ Health Study II cohorts in 1980–2004. Semiquantitative food frequency questionnaires assessed intakes of vitamins A, C, and E and α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin from foods and supplements. The authors examined total antioxidant intake by calculating a “ferric-reducing ability of plasma” score, a new method for quantifying the total antioxidant effect of a food based on the reduction of ferric to ferrous iron by antioxidants. Cumulative updated total energy-adjusted dietary intakes were used. Associations between intake of each nutrient and incident rheumatoid arthritis and systemic lupus erythematosus were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results from the cohorts were pooled meta-analytically by using random-effects models. The authors identified 787 incident rheumatoid arthritis cases and 192 systemic lupus erythematosus cases for whom prospective dietary information was available. In these large, prospective cohorts of women, antioxidant intake was not associated with the risk of developing either rheumatoid arthritis or systemic lupus erythematosus.
doi:10.1093/aje/kwq089
PMCID: PMC2900941  PMID: 20534819
antioxidants; arthritis, rheumatoid; diet; food; lupus erythematosus, systemic; risk factors; vitamins
22.  AMBIENT AIR POLLUTION EXPOSURES AND RISK OF RHEUMATOID ARTHRITIS: RESULTS FROM THE SWEDISH EIRA CASE-CONTROL STUDY 
Annals of the rheumatic diseases  2012;72(6):888-894.
Objective
Environmental factors may play a role in the development of rheumatoid arthritis (RA). We examined whether long-term exposures to air pollution were associated with risk of RA in the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) Study.
Methods
We studied 1,497 incident RA cases and 2,536 controls. Local levels of particulate matter (PM10) and gaseous pollutants (SO2 and NO2,) from traffic and home heating were predicted for all residential addresses. We examined the association of an interquartile range increase (2μg/m3 for PM10, 8μg/m3 for SO2, and 9μg/m3 for NO2) in each pollutant at different time points prior to symptom onset and average exposure with the risk of all RA and the risk of the rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) RA phenotypes.
Results
There was no evidence of an increased risk of RA with PM10. Total RA risks were modestly elevated for the gaseous pollutants, but were not statistically significant after adjustment for smoking and education (odds ratio (OR)=1.18 [95%confidence interval (CI): 0.97–1.43] and OR=1.09 [95%CI: 0.99–1.19] for SO2 and NO2 in the 10th year before onset). Stronger elevated risks were observed for individuals with less than a university education and with the ACPA- RA phenotype.
Conclusion
No consistent overall associations between air pollution in the Stockholm area and risk for RA were observed. However, there was a suggestion of increased risks of RA incidence with increases in NO2 from local traffic and SO2 from home heating sources with stronger associations for the ACPA- phenotype.
doi:10.1136/annrheumdis-2012-201587
PMCID: PMC3654032  PMID: 22833374
air pollution; rheumatoid arthritis; traffic pollution; home heating pollution
24.  Early Life Factors and Adult-Onset Rheumatoid Arthritis 
The Journal of rheumatology  2009;37(1):32-37.
Purpose
Early life factors have been associated with risk of developing autoimmune disease in adulthood. We investigated the association of preterm birth and being breastfed with the incidence of rheumatoid arthritis (RA) in two large prospective cohorts.
Methods
We studied participants from the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII) who provided information on perinatal factors. The NHS (n=121,701) and NHSII (n=116,608) are large prospective cohorts of women followed since 1976 and 1989, respectively. Incident RA was confirmed using the American College of Rheumatology criteria and a medical record review. Cox models were used to estimate the hazard ratio of RA associated with being born preterm, being breastfed, and its duration, adjusting for potential confounders. Random effects meta-analytic methods were used to compute combined estimates from the two cohorts.
Results
We found no statistically significant association between preterm birth and incident RA (RR=1.1, 95% CI: 0.8, 1.5). Being breastfed was not associated with increased incidence of RA (RR=1.0, 95% CI: 0.7, 1.4), regardless of the breastfeeding duration.
Conclusion
In these cohorts of women, neither being preterm birth nor breastfed were associated with the onset of RA.
doi:10.3899/jrheum.090237
PMCID: PMC2800173  PMID: 19833745
25.  End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1 
Objective
Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.
Methods
APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.
Results
Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10−9), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10−6). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ~2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).
Conclusion
APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
doi:10.1002/art.38220
PMCID: PMC4002759  PMID: 24504811

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