Karen H Costenbader

Brigham and Women's Hospital | BWH · Division of Rheumatology, Immunology, and Allergy

Objective Dietary intake is a complex exposure and a potential risk factor for systemic lupus erythematosus (SLE) due to its impact on lipid and glucose metabolism, oxidative stress, and the intestinal microbiome. We aimed to test whether a prudent dietary pattern is associated with a lower risk of SLE, and whether a Western dietary pattern is asso...

Background This 4 phase project¹ jointly supported by EULAR and ACR has led to draft criteria.² Objectives To simplify and validate the new criteria in a large international cohort. Methods 23 expert centres each contributed up to 100 patients with SLE and with non-SLE diagnoses. Diagnoses were verified by 3 independent reviewers for 1,193 SLE an...

Background Macrophage activation syndrome (MAS) is an uncommon but serious complication of systemic lupus erythematosus (SLE). We aimed to identify factors associated with MAS among adult hospitalized SLE patients. Methods Within the Brigham and Women’s Hospital (BWH) Lupus Center Registry, we identified adult SLE patients > age 17 who had been ho...

Objective: Racial variation in total knee replacement (TKR) utilization in the United States has been reported in administrative database studies. We investigated racial variation in TKR procedures in a diverse cohort with severe knee pain followed in an ongoing clinical trial. Methods: VITAL (VITamin D and OmegA-3 TriaL) is a nationwide, random...

Objective: We investigated whether weight change during the early RA period was associated with subsequent mortality and evaluated for an RA-specific effect. Methods: We identified incident RA during the Nurses' Health Study (1976-2016) and created a comparison cohort, matching each RA case with up to 10 non-RA comparators by age and year of RA...

Objective: While systemic lupus erythematosus (SLE) and lupus nephritis (LN) disproportionately affect females, prior studies suggest that males may experience poorer outcomes. We investigated sex differences in healthcare utilization, end-stage renal disease (ESRD) and mortality among patients with LN receiving Medicaid, public insurance for low-...

Objective: To determine the effect of disclosure of rheumatoid arthritis (RA) risk personalized with genetics, biomarkers, and lifestyle factors on health behavior intentions. Methods: We performed a randomized controlled trial among first-degree relatives without RA. Subjects assigned to the Personalized Risk Estimator for RA (PRE-RA) group rec...

Objectives: To compare the performance of LFA-REAL to SLE disease activity assessments and compare scores between trained lupus clinical investigators and clinicians. Methods: Investigators scored the SLEDAI, BILAG, PGA, and LFA-REAL, while the clinicians scored the LFA-REAL. The level of agreement between physicians and instruments was determin...

Objectives Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, subtyped according to clinical manifestations and autoantibodies. Evidence concerning cigarette smoking and SLE risk has been conflicting. We investigated smoking and SLE risk, overall and by anti-double stranded DNA (dsDNA) presence, in two prospective cohort stud...

Objective Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods GWAS data on European Caucasians from the Interna...

OBJECTIVE: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. METHODS: GWAS data on European Caucasians from the Intern...

Objective: We investigated whether RA increases risk for chronic obstructive pulmonary disease (COPD) or asthma independent of factors occurring before RA onset or mediating these respiratory morbidities after diagnosis, such as cigarette smoking. Methods: Within the prospective Nurses' Health Study (n = 121,701 women; 1976-2014), we identified...

Objective: To conduct the first longitudinal study examining whether trauma exposure and PTSD are associated with increased risk of incident SLE in a civilian cohort. Methods: We examined the association of trauma exposure and PTSD symptoms with SLE incidence over 24 years of follow-up in a U.S. longitudinal cohort of women (N=54,763). Incident...

Objectives: We aimed to define candidate criteria within multi-phase development of SLE classification criteria, jointly supported by EULAR and ACR. Prior steps included item generation and reduction by Delphi exercise, further narrowed to 21 items in a Nominal Group Technique exercise. Our objectives were to apply an evidence-based approach to th...

Background Studies of the epidemiology and outcomes of avascular necrosis (AVN) require accurate case-finding methods. The aim of this study was to evaluate performance characteristics of a claims-based algorithm designed to identify AVN cases in administrative data. Methods Using a centralized patient registry from a US academic medical center, w...

Antiphospholipid syndrome (APS) is characterized by thrombosis and/or pregnancy morbidity in patients with persistent antiphospholipid antibodies (aPL). Classification of antiphospholipid syndrome (APS) currently is based on clinical and laboratory criteria identified in the “Sapporo Classification Criteria.” Given significant limitations of the cu...

Objective: Systemic Lupus Erythematosus (SLE) is more prevalent with more severe outcomes among Blacks, Asians, and Hispanics than Whites. Cardiovascular disease (CVD) is the leading cause of death among SLE patients. We examined racial/ethnic variation in risk of CVD events among SLE patients. Methods: Within Medicaid Analytic eXtract (2000-201...

Background EULAR and ACR are supporting multi-phase development of SLE classification criteria based on weighted criteria and a continuous probability scale. Prior steps included criteria generation, criteria reduction through Delphi and Nominal Group Technique exercises, literature review for sensitivity/specificity of candidate criteria, and orga...

Background: Obesity is increasingly prevalent and related to increased risk of several autoimmune diseases, likely via generation of inflammatory adipokines. Prior studies have not evaluated obesity in relation to systemic lupus erythematosus (SLE) risk. We prospectively evaluated whether obesity was associated with increased SLE risk among women...

Objective: To investigate the nationwide prevalence and incidence of serious infections among children with systemic lupus erythematosus (SLE) enrolled in Medicaid, the U.S. health insurance program for low-income patients. Methods: From Medicaid claims (2000-2006) we identified children 5 to <18 years old with SLE (≥3 ICD-9 codes of 710.0, each...

Objectives: To evaluate the association between long-term dietary quality, measured by the 2010 Alternative Healthy Eating Index, and risk of rheumatoid arthritis (RA) in women. Methods: We prospectively followed 76 597 women in the Nurses' Health Study aged 30-55 years and 93 392 women in the Nurses' Health Study II aged 25-42 years at baseline...

Objective: To investigate whether menopausal factors are associated with development of serologic rheumatoid arthritis (RA) phenotypes. Methods: Data were analyzed from Nurses' Health Studies (NHS, 1976-2010; NHSII 1989-2011). In NHS 120,700 female nurses aged 30-55 and in NHSII 116,430 female nurses aged 25-42 were followed via biennial questio...

Objectives: The aim of the present study was to examine the associations between circulating carotenoids and future risk of rheumatoid arthritis (RA). Methods: We conducted a nested case-control study consisting of 227 incident RA cases and 671 matched controls with prospectively measured plasma carotenoids (α-carotene, β-carotene, β-cryptoxanth...

Objective: Systemic lupus erythematosus (SLE) and other autoimmune diseases cause significant morbidity. Identifying populations at risk of developing SLE is essential to curtail irreversible inflammatory damage. The objective of this study was to identify factors associated with transition to classified disease that inform SLE risk. Methods: Pr...

We appreciate the comments about our recent paper on pesticides and other farming exposures in relation to rheumatoid arthritis (RA) in female spouses in the Agricultural Health Study (AHS). In their letter, Murphy et al. suggest that heavy metals, such as manganese and cadmium, may account for observed associations of RA with the fungicide maneb/m...

Background: While infection burden among patients with SLE is high, uncertainty exists about whether rates differ by immunosuppressive drug regimens. We compared infection rates among patients with SLE newly initiating immunosuppressive therapy either using mycophenolate mofetil (MMF), azathioprine (AZA), or cyclophosphamide (CYC). Methods: With...

Objective: Overweight/obesity and anti-citrullinated protein antibodies (ACPA) increase rheumatoid arthritis (RA) risk. We investigated the relationship between body mass index (BMI) and ACPA, tested for an interaction between BMI and ACPA for RA risk, and examined effects of BMI and ACPA on time to RA diagnosis. Design: Within the Nurses' Healt...

Purpose of review: This review examines evidence relating environmental factors to the development of systemic lupus erythematosus (SLE). Recent findings: The strongest epidemiologic evidence exists for the associations of silica, cigarette smoking, oral contraceptives, postmenopausal hormone therapy and endometriosis, with SLE incidence. Recent...

Background: Farming has been associated with rheumatoid arthritis (RA), but the role of pesticides is not known. Objectives: We examined associations between RA and pesticides or other agricultural exposures among female spouses of licensed pesticide applicators in the Agricultural Health Study. Methods: Women were enrolled 1993-1997 and follo...

Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus that disproportionately affects nonwhites and those in lower socioeconomic groups. This review discusses recent data on the incidence, prevalence, and outcomes of patients with lupus nephritis with a focus on low-income US Medicaid patients. We also review recent g...

Background: Using American College of Rheumatology (ACR) and Systemic Lupus (SLE) International Collaborating Clinics (SLICC) criteria for SLE classification as gold standards, we determined sensitivity, specificity, positive and negative predictive values (PPV and NPV) of having SLE denoted as the primary cause of end-stage renal disease (ESRD) i...

Background Criteria for the classification of SLE are being developed with the support of EULAR and ACR. Two independent exercises (expert-based Delphi exercise and data-driven cohort evaluation of early SLE and controls) were undertaken to generate candidate criteria, and then reduce them to a smaller set. Objectives To select a set of items that...

Background Belimumab, a B-lymphocyte stimulator, was FDA-approved March 2011 for the treatment of adult patients with active, autoantibody-positive SLE receiving standard of care medications. There is a need to evaluate belimumab's effectiveness in real-world practice settings. Objectives To describe the effectiveness of initiating belimumab treat...

Background Current SLE classification criteria may not classify patients with early SLE well. SLE mimickers can have an initial presentation similar to SLE and need to be distinguished from early SLE patients by classification criteria. Objectives To describe the clinical and serological presenting manifestations of SLE at disease onset and those...

Background Obesity in the U.S. has increased to an alarming extent over the past four decades. Obesity is related to risk of several autoimmune diseases, possibly via generation of adipokines and inflammatory cytokines. Prospective studies of obesity and systemic lupus erythematosus (SLE) risk are lacking however. Objectives To prospectively evalu...

Systemic lupus erythematosus (SLE) is a disease of reproductive-age women, and thus questions regarding how disease influences pregnancy outcomes arise. We investigated whether five specific types of SLE activity during the 6 months before conception or during pregnancy (nephritis, cytopenias, skin disease, arthritis, serositis) were associated wit...

Patients with rheumatoid arthritis (RA) often inquire about dietary interventions to improve RA symptoms. Although the majority of studies of diet and RA were published prior to the start of the twenty-first century, this review discusses the evidence for a relationship between diet, in particular omega-3 fatty acid supplements, vitamin D supplemen...

Objective: The chronicity and severity of childhood-onset systemic lupus erythematosus (cSLE) necessitate effective transition from pediatric to adult providers. We studied transition outcomes in a cSLE cohort. Methods: We identified patients at an adult lupus clinic diagnosed with SLE ≤ 18 years who had been followed by a pediatric rheumatologi...

Objective: To examine whether genetic, environmental, and serologic rheumatoid arthritis (RA) risk factors are associated with inflammatory joint signs (IJS) in a cohort of RA first-degree relatives (FDRs). Methods: We evaluated RA risk factors and IJS in a prospective cohort of FDRs without RA in the Studies of the Etiology of RA. Genetic facto...

Objective: To prospectively examine the association between leukocyte telomere length (LTL) and subsequent rheumatoid arthritis (RA) development in women. Methods: Using a case-control design nested within the prospective Nurses' Health Study (NHS), NHS II (NHSII), and Women's Health Study (WHS), each validated case of RA with a prediagnostic bl...

Objective: To investigate the association between the presence of aPL and/or LA and all-cause mortality among end-stage renal disease (ESRD) patients with and without SLE. Methods: We included ESRD patients >18 years old followed at an urban tertiary care centre between 1 January 2006 and 31 January 2014 who had aPL measured at least once after...

Keywords: cardiovascular disease and systemic lupus erythematosus (SLE) Background/Purpose: Heart failure (HF) is a leading cause of hospital admissions. In the US, Blacks have higher HF prevalence than other racial/ethnic groups. Cardiovascular disease (CVD) risks are elevated in SLE, but racial/ethnic variation in HF prevalence in SLE has not be...

Background/Purpose: The most common and clinically and histologically best-characterized SLE kidney disease is lupus nephritis (LN). However, other forms of kidney disease can and do occur concomitantly with LN, although their prevalence, clinical features and impact on disease course and response to therapy are not well described. We sought to det...

Objective: To evaluate rheumatoid arthritis (RA) and mortality risk among women followed prospectively in the Nurses' Health Study (NHS). Methods: We analyzed 119,209 women in the NHS that reported no connective tissue disease at enrollment in 1976. Comorbidity and lifestyle data were collected through biennial questionnaires. Incident RA cases...

To examine the association between symptoms of post-traumatic stress disorder (PTSD) and rheumatoid arthritis (RA) risk in a prospective cohort and to characterize the role of smoking in this relationship. A subset (N = 54,224) of the Nurses' Health Study II, a prospective cohort of female nurses, completed the Brief Trauma Questionnaire and a scre...

The aetiologies of endometriosis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are all characterised by immune dysfunction. SLE and RA occur more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. However, only one previous study has evaluated the temporal association between e...

To examine monocyte chemotactic protein-1 (MCP-1) concentration and future rheumatoid arthritis (RA) risk, and investigate effect modification by human leukocyte antigen-shared epitope (HLA-SE) and several lifestyle factors. We conducted a nested case-control study using stored plasma samples from the Nurses' Health Studies. Each pre-RA case was ma...

This study aimed to refine the interaction between cigarette smoking and human leukocyte antigen (HLA) polymorphisms in seropositive rheumatoid arthritis (RA), in the context of a recent amino-acid based HLA model for RA susceptibility. We imputed HLA amino acids and classical alleles from case-control Immunochip array data of 3,588 Swedish Epidemi...

We examined whether nonadherence to hydroxychloroquine (HCQ) or immunosuppressive medications (IS) was associated with higher subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus (SLE). We utilized U.S. Medicaid data from 2000-2006 to identify adults 18-64 years with SLE who were new users of HCQ or IS. W...

Genetic and environmental factors interact in the pathogenesis of autoimmune diseases, including RA. Epidemiologic research over the past few decades has identified several lifestyle and environmental factors that are related to increased risk of developing RA, including cigarette smoking, exposure to crystalline silica, obesity, and most recently...

Background Currently, the classification of APS is based on clinical and laboratory criteria originally published in 1999 (Sapporo classification) [1] and updated in 2006 [2]. Objectives To assess the need for new APS classification criteria. Methods Based on the Task Force (TF) reports of the 14th International Congress on Antiphospholipid Antibod...

Past studies have focused on aggregate lupus disease activity during pregnancy and have produced conflicting results. Our study evaluated lupus activity based on involvement of five specific organ systems during the six months prior to conception and during pregnancy. We assessed 147 pregnancies among 113 women followed at Brigham and Women's Lupus...

While serious infections are significant causes of morbidity and mortality in systemic lupus erythematosus (SLE), the epidemiology in a nationwide cohort of SLE and lupus nephritis (LN) patients has not been examined. Using the Medicaid Analytic eXtract (MAX) database, 2000-2006, we identified patients 18-64 years with SLE and a subset with LN. We...

Objective: To identify racial and ethnic differences in mortality and cardiovascular (CV) risk among patients with end-stage renal disease (ESRD) due to lupus nephritis (LN). Methods: Within the US ESRD registry (1995-2008), we identified individuals ages >17 years with incident ESRD due to systemic lupus erythematosus. We ascertained demographi...

Objective: Incidence of systemic lupus erythematosus (SLE) is disproportionately high in non-Whites vs. Whites. However, variation in mortality according to race/ethnicity has not been well studied. We examined all-cause mortality by race/ethnicity among SLE patients in Medicaid. Methods: Within the Medicaid Analytic eXtract 2000-2006 from 47 U.S>...

Background/Purpose: SLE patients are at increased stroke risk, but racial/ethnic variation in risk has not been examined in a population-based study.We examined risks by race/ethnicity among SLE patients inMedicaid, the US medical insurance program for the poor. We investigated whether differential loss to follow-up and variation in mortality betwe...

Objective: We assessed the contributions of familial rheumatoid arthritis (RA) or lupus and environmental factors to the risk of RA. Methods: Among 121,700 women in the Nurses' Health Study, 65,457 provided data on familial RA/lupus. Among these, 493 RA cases (301 seropositive and 192 seronegative) were validated. We estimated hazard ratios (HRs...

Rheumatic diseases offer distinct challenges to researchers because of heterogeneity in disease phenotypes, low disease incidence, and geographic variation in genetic and environmental factors. Emerging research areas, including epigenetics, metabolomics, and the microbiome, may provide additional links between genetic and environmental risk factor...

Objective We examined the association between a Mediterranean dietary pattern, as measured by the Alternate Mediterranean Diet Score (aMed), and risk of incident rheumatoid arthritis (RA) in US women.Methods We prospectively followed 83,245 participants from the Nurses' Health Study (NHS; 1980-2008) and 91,393 participants from NHS II (1991-2009) w...

Systemic lupus erythematosus (SLE), like rheumatoid arthritis (RA) and other connective tissue diseases (CTDs), does not develop on the day it is diagnosed. Rather, as rheumatologists know, the onset can be days to years before SLE is clinically diagnosed. The recognition of SLE, a prototypic autoimmune disease with a striking heterogeneity and ran...

Objective: To evaluate the association of alcohol consumption with the risk of rheumatoid arthritis (RA) in 2 large prospective cohorts, the Nurses' Health Study (NHS) and NHSII. Methods: The NHS was established in 1976 and enrolled 121,701 female registered nurses in the US. The NHSII began in 1989, enrolling 116,430 female nurses. Lifestyle an...

Objective: The aim of this study was to examine the relationship between preclinical circulating 25-hydroxyvitamin D [25(OH)D] and RA in two nested case-control studies within the prospective cohort Nurses' Health Study (NHS) and NHS II (NHSII). Methods: We included 166 women with RA and blood specimens collected 3 months to 16 years prior to th...

Objectives To examine the relationship between being overweight or obese and developing rheumatoid arthritis (RA) in two large prospective cohorts, the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII). Methods We followed 109 896 women enrolled in NHS and 108 727 in NHSII who provided lifestyle, environmental exposure and anthropometr...

Background: Sugar-sweetened soda consumption is consistently associated with an increased risk of several chronic inflammatory diseases such as type 2 diabetes and cardiovascular diseases. Whether it plays a role in the development of rheumatoid arthritis (RA), a common autoimmune inflammatory disease, remains unclear. Objective: The aim was to...

Objective To identify factors associated with development of systemic lupus erythematosus (SLE) among patients evaluated at a tertiary care Lupus Center for potential SLE. Methods We identified patients first seen at the Brigham and Women's Hospital Lupus Center between 1 January 1992 and 31 December 2012 and thought to have potential SLE by a boar...

Reviews in this edition of Lupus bring together some of the most exciting research on the roles of environmental factors in the development of systemic lupus erythematosus. They explore the evidence behind some key exposures that have been associated with the risk of lupus. They also signal some real changes in the field, including an increasing fo...

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease whose pathogenesis is thought to involve both genetic and environmental factors. It is possible that common environmental exposures, such as cigarette smoking and alcohol consumption, might modify risk of disease development in certain individuals. Here we aim to review...

Exposure to ultraviolet (UV) radiation is among the environmental factors that have been proposed and studied in association with systemic lupus erythematosus (SLE). While it is known that UV radiation exposure may exacerbate pre-existing lupus, it remains unclear whether UV exposure is a risk factor for the development of SLE. Experimental studies...

We investigated the quality of care and factors associated with variations in care among a national cohort of Medicaid enrollees with incident lupus nephritis. 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...

To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors and known genetic risk factors. We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses' Health Study (NHS, 521 RA cases and 517 controls) and the Epidemiological Investigation of RA (E...