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Julia Simard
Assistant Professor of Health Research and Policy (Epidemiology) and, by courtesy, of Medicine (Immunology & Rheumatology)
Julia Fridman Simard, ScD, is an Assistant Professor of Health Research and Policy in the Epidemiology Division, and, by courtesy, of Medicine in Immunology and Rheumatology at Stanford University School of Medicine.
Dr. Simard earned her Masters and Doctorate of Science in Epidemiology degrees at the Harvard School of Public Health. During that time she trained with investigators at the Section of Clinical Sciences, Division of Rheumatology, Immunology, and Allergy at Brigham and Women's Hospital and the Cardiovascular Epidemiology Research Unit at Beth Israel Deaconess Medical Center. In 2008, Dr. Simard relocated to Sweden to begin a Postdoctoral Fellowship in Clinical Epidemiology at the Karolinska Institutet in Stockholm. She became an Assistant Professor in their Clinical Epidemiology Unit in 2011, and was later honored with a Karolinska Institutet Teaching Award. Leveraging the population-based registers of Sweden, Dr. Simard initiated a national register linkage study to examine the utility of registers in Systemic Lupus Erythematosus (SLE) research and develop an extensive data repository for future epidemiologic investigations.
While maintaining a close collaboration with the Karolinska Institutet, she joined Stanford's Epidemiology faculty as an Assistant Professor in 2013. Dr. Simard' studies outcomes in systemic autoimmune rheumatic diseases, such as malignancy, stroke, infection, and mortality, but has shifted much of her focus to the intersection between reproductive epidemiology and rheumatic disease. In 2014 she was awarded a five-year K career development award from the NIH (NIAMS) to study maternal and fetal outcomes in systemic lupus pregnancy. She is also interested in disentangling social and biological constructs in the reported disparities in SLE with respect to sex, gender, race, and ethnicity, both from the etiologic and outcomes perspectives.
Assistant Professor, Health Research & Policy
Assistant Professor (By courtesy), Medicine - Immunology & Rheumatology
Member, Bio-X
Member, Maternal & Child Health Research Institute (MCHRI)
PostDoc, Karolinska Institutet, Clinical Epidemiology (2010)
ScD, Harvard School of Public Health, Epidemiology (2008)
SM, Harvard School of Public Health, Epidemiology (2004)
BA, University of California at San Diego, Math - Applied Science (1999)
Academic jsimard@stanford.edu
Administrative Contact Renee Miller reneemm@stanford.edu
Intermediate Epidemiologic and Clinical Research Methods
HRP 226 (Win)
Directed Reading in Health Research and Policy
HRP 299 (Aut, Win, Spr, Sum)
HRP 370 (Aut, Win, Sum)
Prior Year Courses
Advanced Epidemiologic and Clinical Research Methods
Titilola Falasinnu
Master's Program Advisor
Melody Chung
Postdoctoral Research Mentor
Distinct phenotype of CD4+ T cells driving celiac disease identified in multiple autoimmune conditions. Nature medicine Christophersen, A., Lund, E. G., Snir, O., Sola, E., Kanduri, C., Dahal-Koirala, S., Zuhlke, S., Molberg, O., Utz, P. J., Rohani-Pichavant, M., Simard, J. F., Dekker, C. L., Lundin, K. E., Sollid, L. M., Davis, M. M. 2019
Combining HLA-DQ-gluten tetramers with mass cytometry and RNA sequencing analysis, we find that gluten-specific CD4+ T cells in the blood and intestines of patients with celiac disease display a surprisingly rare phenotype. Cells with this phenotype are also elevated in patients with systemic sclerosis and systemic lupus erythematosus, suggesting a way to characterize CD4+ T cells specific for disease-driving antigens in multiple autoimmune conditions.
New-onset non-infectious pulmonary manifestations among patients with systemic lupus erythematosus in Sweden. Arthritis research & therapy Forbess, L. J., Rossides, M., Weisman, M. H., Simard, J. F. 2019; 21 (1): 48
OBJECTIVE: The objective was to estimate the incidence of lung disease among patients with systemic lupus erythematosus (SLE).METHODS: Using Swedish register data, we identified patients with SLE and pulmonary diagnoses from the National Patient Register through ICD codes. We matched patients with SLE with individuals from the general population. Patients with SLE with a history of pulmonary disease were excluded. Incidence rates (IR) and 95% confidence intervals (CI) were calculated overall and by type of pulmonary disease for incident (2003-2013) and prevalent SLE separately. Hazard ratios (HR) and 95% CI of the association between SLE and pulmonary disease were estimated using adjusted Cox regression models. Sensitivity analyses using a semi-automated approach to quantitative probabilistic bias analysis accounted for potential bias due to unmeasured confounding by smoking.RESULTS: There were 3209 incident and 6908 prevalent cases of SLE identified. The IRs for pulmonary disease were similar in prevalent and incident SLE (14 cases per 1000 person-years). Patients with incident SLE had a nearly sixfold higher rate of pulmonary disease compared to the non-SLE population (HR 5.8 (95% CI 4.8-7.0)). Incident and prevalent SLE was associated with an increased rate of interstitial lung disease (HR 19.0 (95% CI 10.7-34.0) and 14.3 (95% CI 10.8-18.8), respectively). Bias due to unmeasured confounding by smoking was unlikely to explain our findings.CONCLUSION: Lung disease is relatively common in patients with SLE compared to the general population. Clinicians caring for patients with SLE should have heightened suspicion of lung disease, including interstitial lung disease, even early within the disease course or at the time of diagnosis of SLE.
Preterm Delivery Phenotypes in Systemic Lupus Erythematosus Pregnancies. American journal of perinatology Simard, J. F., Chaichian, Y., Rossides, M., Wikstrom, A., Shaw, G. M., Druzin, M. L. 2018
OBJECTIVE: Women with systemic lupus erythematosus (SLE) are at a greater risk of preterm delivery, many of which may be medically indicated (iatrogenic). We investigated preterm delivery phenotypes in SLE and general population comparators and assessed the role of preeclampsia.STUDY DESIGN: We used population-based Swedish Register data (2001-2013) and defined maternal SLE as ≥2 SLE-coded discharge diagnoses from the Patient Register with ≥1 coded by an appropriate specialist. Women from the general population were identified using the Total Population Register. Preterm delivery was defined as <37 weeks and separated into spontaneous and iatrogenic, as well as later versus extremely preterm (32 to <37 weeks vs. <32 weeks). Maternal comorbidity was assessed, and the proportion mediated by preeclampsia was calculated examining first, subsequent, and all pregnancies.RESULTS: Preterm delivery was more common in SLE for the first (22 vs. 6%) and subsequent (15 vs. 4%) pregnancies among 781 SLE-exposed pregnancies and 11,271 non-SLE pregnancies. Of SLE-exposed first births, 27% delivered before 32 weeks, and 90% were iatrogenic (compared with 47% of non-SLE first births).CONCLUSION: Preterm delivery complicates a greater proportion of SLE pregnancies than general population pregnancies, and a considerable proportion of risk is mediated through preeclampsia.
Response to: 'Increased stroke incidence in systemic lupus erythematosus patients: risk factors or disease itself?' by Bruzzese and Zullo ANNALS OF THE RHEUMATIC DISEASES Arkema, E. V., Rossides, M., Von Euler, M., Svenungsson, E., Sjowall, C., Simard, J. F. 2018; 77 (10): e72
View details for DOI 10.1136/annrheumdis-2017-212604
Asthma in Children of Mothers With Systemic Lupus Erythematosus and the Role of Preterm Birth ARTHRITIS CARE & RESEARCH Rossides, M., Nguyen, C., Arkema, E. V., Simard, J. F. 2018; 70 (8): 1269–74
Systemic lupus erythematosus (SLE) and asthma share inheritable IgE-related pathophysiology, but the association between maternal SLE and asthma in the offspring has not been explored. Our aim was to investigate the association between maternal SLE during pregnancy and childhood asthma and examine the role of preterm birth as a mediator of the association using Swedish register data.Information on 12,000 singleton live births (2001-2013) was collected from the Medical Birth Register. Childhood asthma was defined as at least 1 International Classification of Diseases-coded visit in the National Patient Register. Prevalent maternal SLE at delivery was identified from the Medical Birth Register and the National Patient Register. Risk ratios for asthma were estimated while controlling for confounders. Mediation analysis was used to estimate what percentage of the total effect can be explained by preterm birth (defined as either <34 or <37 weeks of gestation).We compared 775 children born to mothers with SLE with 11,225 born to mothers without SLE. Ninety seven children of mothers with SLE (13%) were diagnosed with asthma, compared to 1,211 in the unexposed group (11%). The risk ratio for childhood asthma was 1.46 (95% confidence interval 1.16-1.84). In mediation analysis, 20-29% of the total effect of SLE was explained by preterm birth.Prevalent maternal SLE during pregnancy is associated with an increased risk of asthma in the offspring. While preterm birth can explain a fair proportion of this association, additional unidentified mechanisms also likely play a role.
View details for DOI 10.1002/acr.23472
Impairment of Motivational Efforts: Another Complication of Opioid Compromise of Sleep Quality? Reply JOURNAL OF RHEUMATOLOGY Rossides, M., Simard, J. F., Svenungsson, E., Von Euler, M., Arkema, E. V. 2018; 45 (7): 1070
View details for DOI 10.3899/jrheum.180122
DEMOGRAPHICS AND PRESENTING ORGAN INVOLVEMENT IN A COHORT OF PATIENTS WITH SARCOIDOSIS Sheth, K., Jeyashanmugaraja, G., Simard, J., Shoor, S. BMJ PUBLISHING GROUP. 2018: 509–10
View details for DOI 10.1136/annrheumdis-2018-eular.6164
Use of Administrative Databases to Assess Reproductive Health Issues in Rheumatic Diseases RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Vinet, E., Chakravarty, E. F., Simard, J. F., Clowse, M. 2018; 44 (2): 327-+
Administrative databases, registers, and other sources of big data can be interesting sources to address important research questions on reproduction in women with rheumatic diseases. There are many different types of administrative datasets worldwide, and it is important to understand the type of data present and unavailable in each dataset, validity and potential misclassification of data, and the ability to link maternal data with infant data. This article discusses the advantages and methodologic issues associated with administrative database use for the conduct of observational studies on reproductive issues in women with rheumatic diseases.
View details for DOI 10.1016/j.rdc.2018.01.008
Autoantibody Profiling in Lupus Patients using Synthetic Nucleic Acids SCIENTIFIC REPORTS Klecka, M., Thybo, C., Macaubas, C., Solov'yov, I., Simard, J., Balboni, I., Fox, E., Voss, A., Mellins, E. D., Astakhova, K. 2018; 8: 5554
Autoantibodies to nuclear components of cells (antinuclear antibodies, ANA), including DNA (a-DNA), are widely used in the diagnosis and subtyping of certain autoimmune diseases, including systemic lupus erythematosus (SLE). Despite clinical use over decades, precise, reproducible measurement of a-DNA titers remains difficult, likely due to the substantial sequence and length heterogeneity of DNA purified from natural sources. We designed and tested a panel of synthetic nucleic acid molecules composed of native deoxyribonucleotide units to measure a-DNA. ELISA assays using these antigens show specificity and reproducibility. Applying the ELISA tests to serological studies of pediatric and adult SLE, we identified novel clinical correlations. We also observed preferential recognition of a specific synthetic antigen by antibodies in SLE sera. We determined the probable basis for this finding using computational analyses, providing valuable structural information for future development of DNA antigens. Synthetic nucleic acid molecules offer the opportunity to standardize assays and to dissect antibody-antigen interactions.
Hydroxychloroquine and Preeclampsia Risk in Pregnancies with Systemic Lupus Erythematosus. Do, S. C., Simard, J. F., Druzin, M. L. SAGE PUBLICATIONS INC. 2018: 239A–240A
Paid Family and Childbearing Leave Policies at Top US Medical Schools JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Riano, N. S., Linos, E., Accurso, E. C., Sung, D., Linos, E., Simard, J. F., Mangurian, C. 2018; 319 (6): 611–14
Do Death Certificates Underestimate the Burden of Rare Diseases? The Example of Systemic Lupus Erythematosus Mortality, Sweden, 2001-2013. Public health reports (Washington, D.C. : 1974) Falasinnu, T., Rossides, M., Chaichian, Y., Simard, J. F. 2018: 33354918777253
OBJECTIVES: Mortality due to rare diseases, which are substantial sources of premature mortality, is underreported in mortality studies. The objective of this study was to determine the completeness of reporting systemic lupus erythematosus (SLE) as a cause of death.METHODS: In 2017, we linked data on a Swedish population-based cohort (the Swedish Lupus Linkage, 2001-2013) comprising people with SLE (n = 8560) and their matched general population comparators (n = 37717) to data from the Cause of Death Register. We reviewed death records of deceased people from the cohort (n = 5110) and extracted data on patient demographic characteristics and causes of death. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for not reporting SLE as a cause of death by using multivariable-adjusted logistic regression models.RESULTS: Of 1802 deaths among SLE patients in the study, 1071 (59%) did not have SLE reported on their death records. Most SLE decedents were aged 75-84 at death (n = 584, 32%), female (n = 1462, 81%), and born in Nordic countries (n = 1730, 96%). Decedents aged ≥85 at death were more likely to have SLE not reported on their death records than were decedents aged <50 (OR = 2.34; 95% CI, 1.48-3.68). Having renal failure listed as a cause of death decreased the likelihood of SLE not being reported on the death record (OR = 0.54; 95% CI, 0.40-0.73), whereas having cancer listed as a cause of death increased this likelihood (OR = 2.39; 95% CI, 1.85-3.07).CONCLUSIONS: SLE was greatly underreported as a cause of mortality on death records of SLE patients, particularly in older decedents and those with cancer, thereby underestimating the true burden of this disease. Public health resources need to focus on improving the recording of rare diseases in order to enhance the epidemiological utility of mortality data.
View details for DOI 10.1177/0033354918777253
The Representation of Gender and Race/Ethnic Groups in Randomized Clinical Trials of Individuals with Systemic Lupus Erythematosus. Current rheumatology reports Falasinnu, T., Chaichian, Y., Bass, M. B., Simard, J. F. 2018; 20 (4): 20
This review evaluated gender and race/ethnic representation in randomized controlled trials (RCTs) of patients with systemic lupus erythematosus (SLE).Whites comprise 33% of prevalent SLE cases and comprised 51% of RCT enrollees. Blacks encompass 43% of prevalent SLE cases, but only represented 14% of RCT enrollees. Hispanics comprise 16% of prevalent SLE cases and 21% of RCT enrollees, while Asians comprise 13% of prevalent SLE cases and 10% of RCT enrollees. Males encompass 9% of SLE cases and 7% of RCT enrollees. The reporting and representation of males have remained stable over time, although their representation in RCTs is slighter lower than the prevalence of SLE in males. The representation of Hispanics, Asians, and Native Americans increased over time. However, the representation of blacks among RCT participants has decreased since 2006-2011. RCTs among SLE patients need larger sample sizes in order to evaluate heterogeneity in outcomes among racial subgroups. It is imperative that novel strategies be developed to recruit racial minorities with SLE by identifying and improving barriers to RCT enrollment in order to better understand the disease's diverse population.
Mortality and Functionality after Stroke in Patients with Systemic Lupus Erythematosus JOURNAL OF RHEUMATOLOGY Rossides, M., Simard, J. F., Svenungsson, E., von Euler, M., Arkema, E. V. 2017; 44 (11): 1590–96
To investigate mortality and functional impairment after stroke in systemic lupus erythematosus (SLE).Using Swedish nationwide registers, we identified 423 individuals with SLE and 1652 people without SLE who developed a first-ever ischemic or hemorrhagic stroke (1998-2013) and followed them until all-cause death or for 1 year. HR for death after ischemic or hemorrhagic stroke and the risk ratio of functional impairment (dependence in either transferring, toileting, or dressing) 3 months after ischemic stroke were estimated.One year after stroke, 22% of patients with SLE versus 16% of those without SLE died. After ischemic stroke, patients with SLE had an increased risk of death (HR 1.85, 95% CI 1.39-2.45), which was attenuated after controlling for SLE-related comorbidities (HR 1.41, 95% CI 1.04-1.91). Functional impairment at 3 months was increased in SLE by almost 2-fold (risk ratio 1.73, 95% CI 1.16-2.57). After hemorrhagic stroke, patients with SLE had an HR of 2.30 (95% CI 1.38-3.82) for death, which was increased even during the first month.Compared to subjects without SLE, mortality after ischemic stroke increases after the first month in individuals with SLE, and functionality is worse at 3 months. SLE is associated with all-cause death after hemorrhagic stroke even during the first month. A shift of focus to patient functionality and prevention of hemorrhagic strokes is required.
Determinants of Anti-Tumor Necrosis Factor Drug Use in Juvenile Spondyloarthropathy and Impact on Clinical Disease Outcomes Oliver, M., Simard, J. F., Gerstbacher, D., Lee, T., Sandborg, C. WILEY. 2017
Unraveling Race and Social Context in Understanding Disparities in Lupus Mortality in the United States Falasinnu, T., Chaichian, Y., Palaniappan, L., Simard, J. F. WILEY. 2017
Rates of New-Onset Pulmonary Disease Among Patients with Systemic Lupus Erythematosus in Sweden Forbess, L. J., Weisman, M., Simard, J. F. WILEY. 2017
Preeclampsia and Incident Cardiovascular Disease in SLE Pregnancy Simard, J. F., Rossides, M., Arkema, E. V., Svenungsson, E., Wikstrom, A., Mittleman, M., Salmon, J. E. WILEY. 2017
Preterm Delivery Phenotypes in SLE Pregnancies Simard, J. F., Chaichian, Y., Rossides, M., Wikstrom, A., Shaw, G. M., Druzin, M. WILEY. 2017
Preterm Birth Phenotypes in Women with Autoimmune Diseases Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. WILEY. 2017
Do Death Certificates Underestimate the Burden of Rare Diseases: The Example of Systemic Lupus Erythematosus Mortality in Sweden Falasinnu, T., Rossides, M., Chaichian, Y., Simard, J. F. WILEY. 2017
Stroke in systemic lupus erythematosus: a Swedish population-based cohort study. Annals of the rheumatic diseases Arkema, E. V., Svenungsson, E., von Euler, M., Sjöwall, C., Simard, J. F. 2017
To study the occurrence of ischaemic and haemorrhagic stroke in systemic lupus erythematosus (SLE) compared with the general population by age, sex and time since SLE diagnosis METHODS: Adults with incident SLE were identified from the Swedish National Patient Register (NPR, n=3390) and general population comparators from the Total Population Register were matched on age, sex and county (n=16730). Individuals were followed prospectively until first of death, December 2013, emigration or incident stroke (identified from the NPR, Cause of Death Register and the Stroke Register). Incidence rates, rate differences and HR were estimated comparing SLE with non-SLE. Estimates were stratified by sex, age and time since diagnosis.We observed 126 strokes in SLE and 304 in the general population. Individuals with SLE had a twofold increased rate of ischaemic stroke compared with the general population (HR 2.2; 95% CI 1.7 to 2.8). The HR for intracerebral haemorrhage was 1.4 (95% CI 0.7 to 2.8). There was effect modification by sex and age, with the highest HRs for females and individuals <50 years old. The HR for ischaemic stroke was highest in the first year of follow-up (3.7; 95% CI 2.1 to 6.5).The relative risk of ischaemic stroke in SLE was more than doubled compared with the general population, and importantly, the highest relative risks were observed within the first year after SLE diagnosis. Thus, the first encounter with patients presents an opportunity for rheumatologists to screen for risk factors and intervene.
Cervical neoplasia in systemic lupus erythematosus: a nationwide study RHEUMATOLOGY Wadstrom, H., Arkema, E. V., Sjowall, C., Askling, J., Simard, J. F. 2017; 56 (4): 613-619
View details for DOI 10.1093/rheumatology/kew459
Medication use among pregnant women with systemic lupus erythematosus and general population comparators RHEUMATOLOGY Palmsten, K., Simard, J. F., Chambers, C. D., Arkema, E. V. 2017; 56 (4): 561-569
The aim was to characterize SLE medication trends before, during and after pregnancy and to compare other commonly used medications during SLE pregnancies with non-SLE pregnancies.Women with pregnancies ending in live birth or stillbirth were identified from the Swedish Medical Birth Register (2006-12). National registers were used to identify women with prevalent SLE during pregnancy and a sample without SLE and to identify prescription medications dispensed from 3 months pre-pregnancy until 6 months postpartum. We reported the prevalence of DMARDs, systemic CSs and NSAIDs (aspirin reported separately) in SLE pregnancies. We calculated prevalence estimates of other medications that were dispensed during pregnancy to ⩾ 5% of SLE pregnancies and for the same medications among non-SLE pregnancies.There were 483 pregnancies among women with SLE and 5723 pregnancies among women without SLE. In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy; the prevalence was 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs and varied by pregnancy period. The prevalence of common medications among SLE pregnancies was 1.2- to 20-fold higher than among non-SLE pregnancies; for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%) and levothyroxine (15.9 vs 4.9%).In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Commonly used medications in SLE pregnancies had far higher prevalence estimates compared with non-SLE pregnancies. Research regarding benefits and risks of commonly used medications on SLE pregnancies, breast milk and long-term outcomes for offspring is needed.
Early-onset Preeclampsia in Lupus Pregnancy PAEDIATRIC AND PERINATAL EPIDEMIOLOGY Simard, J. F., Arkema, E. V., Nguyen, C., Svenungsson, E., Wikstrom, A., Palmsten, K., Salmon, J. E. 2017; 31 (1): 29-36
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that occurs during childbearing years and has been associated with preeclampsia. However, little is known about preeclampsia of early onset, which is associated with severe adverse maternal and perinatal outcomes.Using national population-based Swedish registers we identified women with SLE (≥2 visits with corresponding ICD codes) and a sample without SLE who gave birth to singleton infants 2001-12. Risk ratios (RR) and 95% confidence intervals (CI) for early-onset preeclampsia (defined by ICD codes corresponding to preeclampsia registered at <34 weeks) in SLE women were calculated based on adjusted modified Poisson models for first, subsequent, and all pregnancies.Among 742 births to women with SLE and 10 484 births to non-SLE women, there were 32 (4.3%) and 55 (0.5%) diagnoses of early-onset preeclampsia respectively. SLE was associated with an increased risk of early-onset preeclampsia (RR 7.8, 95% CI 4.8, 12.9, all pregnancies). The association remained similar upon restriction to women without pregestational hypertension. Adjustment for antiphospholipid syndrome (APS)-proxy attenuated the association. RRs for early-onset preeclampsia were smaller for subsequent pregnancies (RR 4.7, 95% CI 2.0, 11.2) compared to first and all (see above).Women with SLE are at increased risk of early-onset preeclampsia and this increased risk may be independent of the traditional risk factors such as pregestational hypertension, APS, BMI, or smoking. Women with SLE during pregnancy should be closely monitored for early-onset preeclampsia and future research needs to identify the non-traditional preeclampsia factors that might cause this serious outcome.
View details for DOI 10.1111/ppe.12332
Sex Ratio of Offspring Born to Women With Systemic Lupus Erythematosus or Rheumatoid Arthritis ARTHRITIS & RHEUMATOLOGY Arkema, E. V., Askling, J., Salmon, J. E., Simard, J. F. 2017; 69 (1): 143-147
View details for DOI 10.1002/art.39843
Brief Report: Sex Ratio of Offspring Born to Women With Systemic Lupus Erythematosus or Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) Arkema, E. V., Askling, J., Salmon, J. E., Simard, J. F. 2017; 69 (1): 143-147
To determine whether the sex ratio among offspring born to women with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) is different from that in the general population.Women with a singleton delivery were identified from the Swedish Medical Birth Register (1973-2012) and linked to the National Patient Register (1964-2012) to identify those with prevalent SLE or RA. A sample of general population comparators was identified from the Swedish Total Population Register. We calculated the percentages of males born to women with SLE, women with RA, and women in the general population, as well as the risk ratio (RR) for having a male child among first births and all births. We also examined a history of antiphospholipid syndrome in the SLE population, using International Classification of Disease codes before or at delivery.We identified 661 women with SLE and 1,136 women with RA before their first delivery. There were a total of 1,401 deliveries to women with SLE and a total of 2,674 deliveries to women with RA. Compared with women in the general population, women with SLE and those with RA had a lower risk of having a first-born male (RR 0.92 [95% confidence interval 0.85-1.00] and RR 0.93 [95% confidence interval 0.87-0.99], respectively). Among all births, the percentage of male offspring remained lower than that in the general population, but the difference was not statistically significant for RA.The proportion of male offspring born to women with prevalent SLE or RA at delivery was lower than that in the general population, although the difference was small. Chronic inflammation may affect the sex ratio through fetal loss in early gestation.
Cervical neoplasia in systemic lupus erythematosus: a nationwide study. Rheumatology (Oxford, England) Wadström, H., Arkema, E. V., Sjöwall, C., Askling, J., Simard, J. F. 2016
The aim was to examine the risk of cervical neoplasia in women with SLE, overall and with respect to treatment, compared with women from the general population.By linking national Swedish registers, we assembled a cohort including women with SLE (n = 4976) and matched general population comparators (n = 29 703). Two subcohorts of treated SLE patients were defined on the basis of treatment with antimalarials (n = 1942) and other immunosuppressants (AZA, CYC, ciclosporin, MTX, MMF or rituximab; n = 2175). The main outcome was defined as a first cervical neoplasia (dysplasia or cancer) during follow-up. Secondary outcomes were first cervical intraepithelial neoplasia (CIN) 1; first CIN grades 2-3; and first invasive cervical cancer during follow-up (2006-12). Cox regression models estimated relative risks adjusted for age, level of education, health-care utilization, number of children, marital status, family history of cervical cancer and prior cervical screening.Based on 121 events of cervical neoplasia during 23 136 person-years among SLE patients, there was an increased risk of any cervical neoplasia compared with the general population [hazard ratio (HR) = 2.12 (95% CI: 1.65, 2.71)]. The risk of CIN 1 [HR = 2.33 (95% CI: 1.58, 3.44)], CIN 2-3 [HR = 1.95 (95% CI: 1.43, 2.65)], but not invasive cervical cancer [HR = 1.64 (95% CI: 0.54, 5.02)], was increased in women with SLE. The subcohort treated with other immunosuppressants was at highest risk of cervical neoplasia.SLE is a risk factor for cervical neoplasia, in particular for pre-malignant cervical lesions. Among patients with SLE, the risk is higher among those treated with immunosuppresants compared with those treated with antimalarials.
Medication use among pregnant women with systemic lupus erythematosus and general population comparators. Rheumatology (Oxford, England) Palmsten, K., Simard, J. F., Chambers, C. D., Arkema, E. V. 2016
The Rheumatology Informatics System for Effectiveness (RISE): A National Informatics-Enabled Registry for Quality Improvement. Arthritis care & research Yazdany, J., Bansback, N., Clowse, M., Collier, D., Law, K., Liao, K. P., Michaud, K., Morgan, E. M., Oates, J. C., Orozco, C., Reimold, A., Simard, J. F., Myslinski, R., Kazi, S. 2016
The Rheumatology Informatics System for Effectiveness (RISE) is a national electronic health record (EHR)-enabled registry. RISE passively collects data from EHRs of participating practices, provides advanced quality measurement and data analytic capacities, and fulfills national quality reporting requirements. Here we report the registry's architecture and initial data, and we demonstrate how RISE is being used to improve the quality of care.RISE is a certified Centers for Medicare and Medicaid Services Qualified Clinical Data Registry, allowing collection of data without individual patient informed consent. We analyzed data between October 1, 2014 and September 30, 2015 to characterize initial practices and patients captured in RISE. We also analyzed medication use among rheumatoid arthritis (RA) patients and performance on several quality measures.Across 55 sites, 312 clinicians contributed data to RISE; 72% were in group practice, 21% in solo practice, and 7% were part of a larger health system. Sites contributed data on 239,302 individuals. Among the subset with RA, 34.4% of patients were taking a biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) at their last encounter, and 66.7% were receiving a nonbiologic DMARD. Examples of quality measures include that 55.2% had a disease activity score recorded, 53.6% a functional status score, and 91.0% were taking a DMARD in the last year.RISE provides critical infrastructure for improving the quality of care in rheumatology and is a unique data source to generate new knowledge. Data validation and mapping are ongoing and RISE is available to the research and clinical communities to advance rheumatology.
Endometriosis and systemic lupus erythematosus: a population-based case-control study. Lupus Harris, H. R., Simard, J. F., Arkema, E. V. 2016; 25 (9): 1045-1049
To investigate the association between endometriosis and systemic lupus erythematosus (SLE) in prospectively collected population-based data.We conducted a case-control study using Swedish registers, identifying female SLE cases from the National Patient Register and female controls sampled from the general population matched on birth year, sex and county during 1964-2011. We identified endometriosis diagnoses from the National Patient Register using ICD codes. We estimated odds ratios and 95% confidence intervals using conditional logistic regression models.We identified 2834 cases of SLE and 14,164 controls. Seventy-eight cases were diagnosed with endometriosis prior to their SLE diagnosis and 288 controls were diagnosed prior to the index date. We observed a significant association between endometriosis and subsequent SLE with an odds ratio of 1.39 (95% confidence interval = 1.09-1.78). The association was similar when requiring a laparoscopy/laparotomy within six months of the endometriosis diagnosis (odds ratio = 1.33; 95% confidence interval = 0.84-2.12) while the association was stronger when restricted to endometriosis diagnosed at the same time as hysterectomy (odds ratio = 2.26; 95% confidence interval = 1.47-3.64).Our findings suggest an association between endometriosis and SLE. Future prospective studies with extended follow-up will be necessary to clarify whether this association is influenced by the timing and severity of endometriosis diagnosis.
What to Expect When Expecting With Systemic Lupus Erythematosus (SLE): A Population-Based Study of Maternal and Fetal Outcomes in SLE and Pre-SLE ARTHRITIS CARE & RESEARCH Arkema, E. V., Palmsten, K., Sjowall, C., Svenungsson, E., Salmon, J. E., Simard, J. F. 2016; 68 (7): 988-994
To assess maternal and fetal outcomes associated with subclinical (pre-systemic lupus erythematosus [SLE] and SLE presenting up to 5 years postpartum) and prevalent maternal SLE during pregnancy compared with the general population.This prospective cohort study used population-based Swedish registers to identify 13,598 women with first singleton pregnancies registered in the Medical Birth Register (551 prevalent SLE, 65 pre-SLE within 0-2 years, 133 pre-SLE within 2-5 years, and 12,847 general population). SLE was defined as ≥2 SLE-coded discharge diagnoses in the patient register with ≥1 diagnosis from a specialist. Unadjusted risks of adverse pregnancy or birth outcomes were calculated by SLE status, and Cochran-Armitage tests evaluated trend across exposure groups.Maternal outcomes such as preeclampsia, hypothyroidism, stroke, and infection were more common among women with SLE. Sixteen percent of prevalent-SLE pregnancies were diagnosed with preeclampsia compared with 5% of those from the general population. Among the pre-SLE women, preeclampsia was found in 26% of those with SLE within 2 years postpartum and 13% in those with SLE within 2-5 years postpartum. Similarly, infant outcomes, such as preterm birth, infection, and mortality, were worse among those born to mothers with prevalent SLE and pre-SLE during pregnancy. The test for trend was significant for most outcomes.Our data demonstrate that adverse maternal and fetal outcomes are more common in SLE pregnancies. Furthermore, these unfavorable outcomes are observed in pregnancies occurring prior to the diagnosis of SLE. Thus, the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to these pregnancy complications.
What is the impact of chronic systemic inflammation such as rheumatoid arthritis on mortality following cancer? Annals of the rheumatic diseases Simard, J. F., Ekberg, S., Johansson, A. L., Askling, J. 2016; 75 (5): 862-866
Emerging evidence links inflammation and immune competence to cancer progression and outcome. Few studies addressing cancer survival in the context of rheumatoid arthritis (RA) have reported reduced survival without accounting for the underlying mortality risk in RA. Whether this increased mortality is a cancer-specific phenomenon, an effect of the decreased lifespan in RA or a combination of both remains unknown.Using Swedish register data (2001-2009), we performed a cohort study of individuals with RA (N=34 930), matched to general population comparators (N=169 740), incident cancers (N=12 676) and deaths (N=14 291). Using stratified Cox models, we estimated HRs of death associated with RA in the presence and absence of cancer, by stage and time since cancer diagnosis, for all cancers and specific sites.In the absence of cancer, RA was associated with a doubled mortality rate (HR=2.1, 95% CI 2.0 to 2.2). In the presence of cancer, the relative effect of RA on mortality was varied by stage. For cancer (tumour, node, metastases) stages I and II at diagnosis, the relative effect of RA on mortality was the same as in the absence of cancer. For cancers diagnosed at advanced stages with absolute higher mortality, the effect decreased (HR=1.2, 95% CI 1.1 to 1.3). These associations remained across time since cancer diagnosis and were reasonably similar across cancer sites.Much of the increase in mortality in patients with RA diagnosed with cancer seems to reside with effects of RA independently of the cancer.
Case definitions in Swedish register data to identify systemic lupus erythematosus. BMJ open Arkema, E. V., Jönsen, A., Rönnblom, L., Svenungsson, E., Sjöwall, C., Simard, J. F. 2016; 6 (1)
To develop and investigate the utility of several different case definitions for systemic lupus erythematosus (SLE) using national register data in Sweden.The reference standard consisted of clinically confirmed SLE cases pooled from four major clinical centres in Sweden (n=929), and a sample of non-SLE comparators randomly selected from the National Population Register (n=24,267). Demographics, comorbidities, prescriptions and autoimmune disease family history were obtained from multiple registers and linked to the reference standard. We first used previously published SLE definitions to create algorithms for SLE. We also used modern data mining techniques (penalised least absolute shrinkage and selection operator logistic regression, elastic net regression and classification trees) to objectively create data-driven case definitions. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the case definitions identified.Defining SLE by using only hospitalisation data resulted in the lowest sensitivity (0.79). When SLE codes from the outpatient register were included, sensitivity and PPV increased (PPV between 0.97 and 0.98, sensitivity between 0.97 and 0.99). Addition of medication information did not greatly improve the algorithm's performance. The application of data mining methods did not yield different case definitions.The use of SLE International Classification of Diseases (ICD) codes in outpatient clinics increased the accuracy for identifying individuals with SLE using Swedish registry data. This study implies that it is possible to use ICD codes from national registers to create a cohort of individuals with SLE.
View details for DOI 10.1136/bmjopen-2015-007769
Rheumatoid arthritis, anti-tumour necrosis factor treatment, and risk of squamous cell and basal cell skin cancer: cohort study based on nationwide prospectively recorded data from Sweden. BMJ (Clinical research ed.) Raaschou, P., Simard, J. F., Asker Hagelberg, C., Askling, J. 2016; 352: i262-?
To investigate the risk of squamous cell and basal cell skin cancer in patients with rheumatoid arthritis naive to biologic drugs, in patients starting tumour necrosis factor (TNF) inhibitor treatment, and in the general population.Population based cohort study.Nationwide data from Sweden.Cohort of patients with rheumatoid arthritis naive to biologics (n=46 409), cohort of patients with rheumatoid arthritis starting TNF inhibitor treatment as first biologic in 1998-2012 (n=12 558), and matched general population comparator cohort, identified through national quality of care and health registers.Hazard ratio of first in situ or invasive squamous cell skin cancer (1998-2012) and first basal cell cancer (2004-12).For basal cell cancer, the hazard ratio was 1.22 (95% confidence interval 1.07 to 1.41) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.14 (0.98 to 1.33; 236 v 1587 events) comparing TNF inhibitor treated patients with biologics-naive patients. For squamous cell cancer, the hazard ratio was 1.88 (1.74 to 2.03) comparing biologics-naive rheumatoid arthritis patients with the general population and 1.30 (1.10 to 1.55; 191 v 847 events) comparing TNF inhibitors with biologics-naive patients; the latter translated to an annual number needed to harm in the order of 1600. Among people with a history of squamous cell or basal cell cancer, TNF inhibitors did not further increase risks.A small to moderately increased risk of basal cell cancer was seen in biologics-naive rheumatoid arthritis patients, with no further effect of TNF inhibitors. For squamous cell cancer, the risk was nearly doubled in biologics-naive patients, with a further 30% increase in risk among patients treated with TNF inhibitors; this translates to one additional case for every 1600 years of treatment experience, assuming that this association reflected causality. Vigilance regarding skin malignancies may be advisable in rheumatoid arthritis, irrespective of TNF inhibitor treatment. Most of the increase in risk for non-melanoma skin cancer in patients with rheumatoid arthritis treated with TNF inhibitors originates from factors other than that treatment.
View details for DOI 10.1136/bmj.i262
Perinatal risk factors for future SLE: a population-based nested case-control study LUPUS Arkema, E. V., Simard, J. F. 2015; 24 (8): 869-874
To investigate the association between perinatal characteristics and the offspring's risk of lupus using population-based registers in Sweden.We conducted a nested case-control study, identifying systemic lupus erythematosus (SLE) cases from the National Patient Register and controls sampled from the general population matched on birth year, sex, and residential county. We obtained data on the mother's health and age during pregnancy and characteristics of labor and delivery from the Medical Birth Register (births from 1973 through 2008) for cases and controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression models overall and separately for males and females.We identified 774 cases and 3337 controls. Age at which SLE was first observed ranged from 0 to 36 years old. High birth weight was not a risk factor for SLE and did not differ by sex. Males had a 2.4-fold increased odds of SLE if born preterm (<37 weeks; OR = 2.41; 95% CI 1.09, 5.36). Birth order was significantly associated with SLE, particularly among females (first born vs. not OR = 0.77, 95% CI 0.64, 0.94; continuous birth order OR = 1.12. 95% CI 1.02, 1.24).Being born first was associated with reduced odds of SLE and the odds of SLE increased by 12% for every additional birth. Preterm birth was associated with increased odds in males only. Unlike previous work, high birth weight was not a risk factor for SLE.
Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab ANNALS OF THE RHEUMATIC DISEASES Neovius, M., Arkema, E. V., Olsson, H., Eriksson, J. K., Kristensen, L. E., Simard, J. F., Askling, J. 2015; 74 (2): 354-360
To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA).Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy).During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001).Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy.
Cohort profile: systemic lupus erythematosus in Sweden: the Swedish Lupus Linkage (SLINK) cohort. BMJ open Arkema, E. V., Simard, J. F. 2015; 5 (8)
A cohort of individuals with systemic lupus erythematosus (SLE) was identified through linkage of several national registers to investigate important epidemiological questions using not only population-based data to minimise selection bias, but also to identify matched comparators from the general population to serve as controls. This cohort was established to overcome the general dearth of data in SLE epidemiology.All individuals registered in Sweden with a personal identity number and who have obtained medical care at any hospital or public non-primary outpatient specialist care with suspected SLE were identified. Inpatient register data date back to the 1960s, although complete national coverage of the inpatient register was achieved in 1987. In 2001, the outpatient component was also added to the register, representing the entire country of Sweden. For each suspected individual with SLE, up to five individuals from the general population were identified and matched on sex, birth year and county of residence.We have linked this study population to a number of national and quality registers in Sweden to identify first-degree relatives, deaths, births, dispensed prescriptions, comorbidities and disease end points, such as stroke and cancer, as well as basic health economic data. We found geographic variability in the prevalence of SLE by county. We have also shown that being first-born confers a reduced odds of having SLE in childhood and early adulthood.In addition to updating the national register linkage with several more years of follow-up data, we are adding several quality registers in Sweden, including the Tuberculosis register and the Social Insurance Office database. While these updates are ongoing and additional follow-up accumulates, we are studying a number of outcomes in SLE, including stroke, pregnancy and death. We will continue to present findings at scientific conferences and in the peer-reviewed literature.
Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies. RMD open Holmqvist, M., Simard, J. F., Asplund, K., Arkema, E. V. 2015; 1 (1)
Previous studies of stroke in systemic lupus erythematosus (SLE) have had limited statistical power, combined stroke subtypes into composite outcomes, and lacked a reference population estimate. Therefore, we conducted a systematic review and meta-analysis of cohort studies to summarise the stroke subtype-specific risk in patients with SLE compared to the general population. A systematic search of MEDLINE and EMBASE was performed for cohort studies examining the risk of stroke in SLE and including a general population comparator. Random effects models were used to pool the risk ratio (RR) for stroke. Subgroup analyses were carried out to investigate potential sources of heterogeneity. 10 studies were included which reported RRs for overall stroke (n=5), ischaemic stroke (n=6), intracerebral haemorrhage (n=3) and subarachnoid haemorrhage (n=3). The pooled RR for overall stroke was 2.53 (95% CI 1.96 to 3.26), ischaemic stroke 2.10 (95% CI 1.68 to 2.62), intracerebral haemorrhage 2.72 (95% CI 2.15 to 3.44) and subarachnoid haemorrhage 3.85 (95% CI 3.20 to 4.64). Significant heterogeneity among studies for ischaemic stroke was detected (p=0.002). Relative risk of stroke was highest among individuals younger than 50 years of age. Individuals with SLE have a twofold higher risk of ischaemic stroke, a threefold higher risk of intracerebral haemorrhage, and an almost fourfold higher risk of subarachnoid haemorrhage compared to the general population. Future studies should focus on whether comorbidity and disease flares are related to stroke, when individuals are at the highest risk, and how the targeting of specific groups of patients with SLE may reduce this risk.
View details for DOI 10.1136/rmdopen-2015-000168
Systemic lupus erythematosus prevalence in Sweden in 2010: what do national registers say? Arthritis care & research Simard, J. F., Sjöwall, C., Rönnblom, L., Jönsen, A., Svenungsson, E. 2014; 66 (11): 1710-1717
Worldwide prevalence estimates of systemic lupus erythematosus (SLE) range from 3 to 207 per 100,000, depending on region and population, SLE definition, case sources, and other methodologic considerations. We aimed to determine the prevalence of SLE in Sweden on January 1, 2010, using population-based registers.Linking multiple national registers, we identified all possible inpatient and outpatient visits with SLE-specific discharge diagnoses and relevant prescription dispensations among living individuals registered in Sweden on January 1, 2010. SLE was defined from a lenient classification (requiring only a single visit) to stricter definitions that required multiple visits with a history of relevant specialist care and a dispensation for common SLE medications. Prevalence was calculated overall and by sex, age (0-14 years, 15-49 years, and ≥50 years, as well as in 5-year age groups), and county of residence.Overall prevalence ranged from 46 per 100,000 for the strictest definition to 85 per 100,000 for the least strict definition. As expected, SLE was more common among females (range 79-144 per 100,000) than males (range 12-25 per 100,000) and varied by age. The up to 4-fold variation by county was unexpected. Prevalence generally increased with age (2, 52, and 95 per 100,000 by increasing age group, 0-14 years, 15-49 years, and ≥50 years, respectively, using a moderately strict definition) and also varied by county.Variations of prevalence by age and sex were consistent with previous studies and overall ranged from 46 to 85 per 100,000. We observed a surprising geographic variation in the prevalence of SLE in Sweden on January 1, 2010, according to multiple definitions.
Predictors of work disability during the first 3 years after diagnosis in a national rheumatoid arthritis inception cohort ANNALS OF THE RHEUMATIC DISEASES Olofsson, T., Petersson, I. F., Eriksson, J. K., Englund, M., Simard, J. F., Nilsson, J., Geborek, P., Jacobsson, L. T., Askling, J., Neovius, M. 2014; 73 (5): 845-853
OBJECTIVE: To identify predictors of sick leave and disability pension in patients with early rheumatoid arthritis (RA). METHODS: Individuals aged 19-59 years diagnosed with early RA (≤12 months symptom duration) were identified in the Swedish Rheumatology Quality Register (1999-2007; n=3029). We retrieved days of sick leave and disability pension from the Swedish Social Insurance Agency and baseline predictors of total work days lost during 3 years after RA diagnosis were investigated using linear regression. Due to effect modification by baseline work ability (defined as work days lost the month before diagnosis), analyses were stratified into three categories: full=0 work days lost the month before diagnosis; partial=1-29 work days lost; and none=30 work days lost. RESULTS: 71% of patients with full baseline work ability still had full work ability after 3 years compared with 36% (p<0.001) and 18% (p<0.001) of those with partial and no work ability at baseline, respectively. Elevated baseline levels of HAQ and DAS28, higher age, lower education level and unemployment were associated with more work days lost during 3 years in all strata of baseline work ability (all p<0.05). In a separate analysis, more objective variables (ESR, CRP and swollen joints) were not. Generally, the largest regression coefficients were seen for patients with partial baseline work ability. CONCLUSIONS: Work ability at RA diagnosis was the most important predictor of 3-year sick leave and disability pension. Taking this into account, HAQ, DAS28, age and education level were also significant predictors, whereas ESR and CRP were not.
Association of Varying Number of Doses of Quadrivalent Human Papillomavirus Vaccine With Incidence of Condyloma JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Herweijer, E., Leval, A., Ploner, A., Eloranta, S., Simard, J. F., Dillner, J., Netterlid, E., Sparen, P., Arnheim-Dahlstrom, L. 2014; 311 (6): 597-603
Determining vaccine dose-level protection is essential to minimize program costs and increase mass vaccination program feasibility. Currently, a 3-dose vaccination schedule is recommended for both the quadrivalent and bivalent human papillomavirus (HPV) vaccines. Although the primary goal of HPV vaccination programs is to prevent cervical cancer, condyloma related to HPV types 6 and 11 is also prevented with the quadrivalent vaccine and represents the earliest measurable preventable disease outcome for the HPV vaccine.To examine the association between quadrivalent HPV vaccination and first occurrence of condyloma in relation to vaccine dose in a population-based setting.An open cohort of all females aged 10 to 24 years living in Sweden (n = 1,045,165) was followed up between 2006 and 2010 for HPV vaccination and first occurrence of condyloma using the Swedish nationwide population-based health data registers.Incidence rate ratios (IRRs) and incidence rate differences (IRDs) of condyloma were estimated using Poisson regression with vaccine dose as a time-dependent exposure, adjusting for attained age and parental education, and stratified on age at first vaccination. To account for prevalent infections, models included a buffer period of delayed case counting.A total of 20,383 incident cases of condyloma were identified during follow-up, including 322 cases after receipt of at least 1 dose of the vaccine. For individuals aged 10 to 16 years at first vaccination, receipt of 3 doses was associated with an IRR of 0.18 (95% CI, 0.15-0.22) for condyloma, whereas receipt of 2 doses was associated with an IRR of 0.29 (95% CI, 0.21-0.40). One dose was associated with an IRR of 0.31 (95% CI, 0.20-0.49), which corresponds to an IRD of 384 cases (95% CI, 305-464) per 100,000 person-years, compared with no vaccination. The corresponding IRDs for 2 doses were 400 cases (95% CI, 346-454) and for 3 doses, 459 cases (95% CI, 437-482). The number of prevented cases between 3 and 2 doses was 59 (95% CI, 2-117) per 100,000 person-years.Although maximum reduction in condyloma risk was seen after receipt of 3 doses of quadrivalent HPV vaccine, receipt of 2 vaccine doses was also associated with a considerable reduction in condyloma risk. The implications of these findings for the relationship between number of vaccine doses and cervical cancer risk require further investigation.
View details for DOI 10.1001/jama.2014.95
Challenges in understanding the role of pregnancy morbidity in cardiovascular risk in SLE. Lupus science & medicine Simard, J. F., Yazdany, J. 2014; 1 (1)
View details for DOI 10.1136/lupus-2014-000035
Lifestyle factors, autoimmune disease and family history in prognosis of non-hodgkin lymphoma overall and subtypes INTERNATIONAL JOURNAL OF CANCER Simard, J. F., Baecklund, F., Chang, E. T., Baecklund, E., Hjalgrim, H., Adami, H., Glimelius, B., Smedby, K. E. 2013; 132 (11): 2659-2666
Lifestyle factors and medical history are known to influence risk of non-Hodgkin lymphoma (NHL). Whether these factors affect the prognosis of NHL, especially its subtypes, is unclear. To investigate this, the association between these factors and all-cause and lymphoma-related mortality was assessed in a population-based cohort of 1,523 Swedish NHL patients included in the Scandinavian Lymphoma Etiology study in 1999-2002. Participants contributed time from NHL diagnosis until death or October 1, 2010, with virtually complete follow-up through linkage to the Swedish Cause of Death Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using stratified and multivariable-adjusted Cox regression models. During a median follow-up of 8.8 years, 670 patients (44%) died, with the majority of deaths attributed to lymphoma (86%). Current versus never smoking at diagnosis was associated with increased rate of all-cause death for all NHL (HR = 1.5, 1.2-1.8) and diffuse large B-cell lymphoma (HR = 1.8, 1.2-2.7). Low educational level (HR = 1.3, 1.1-1.7, <9 vs. >12 years) and NHL risk-associated autoimmune disease (HR = 1.4, 1.0-1.8) were associated with death for all NHL combined. However, evidence of an association with lymphoma-related death was limited. Body mass index, recent sunbathing and family history of hematopoietic malignancy were not consistently associated with death after NHL or its specific subtypes. These results add to the evidence that cigarette smoking, socioeconomic status and certain autoimmune diseases affect survival after NHL. Further investigations are needed to determine how these factors should be incorporated into clinical prognostic assessment.
View details for DOI 10.1002/ijc.27944
Incidence of Rheumatoid Arthritis in Sweden: A Nationwide Population-Based Assessment of Incidence, Its Determinants, and Treatment Penetration ARTHRITIS CARE & RESEARCH Eriksson, J. K., Neovius, M., Ernestam, S., Lindblad, S., Simard, J. F., Askling, J. 2013; 65 (6): 870-878
To estimate the nationwide incidence of rheumatoid arthritis (RA) in Sweden, including its variation across age, sex, geography, and demography, and to describe the sensitivity of register-based incidence estimates to different RA case definitions.Incident RA patients were identified using the Swedish National Patient Register. In the base case, incident RA was defined as first-ever inpatient or nonprimary outpatient care visit listing an RA diagnosis in 2006-2008, with a second visit listing RA within 1 year. Patients prescribed disease-modifying antirheumatic drugs more than 6 months prior to the first visit listing RA were not regarded as incident. The robustness of this definition was evaluated by more liberal and strict criteria, and by penetration of antirheumatic treatment.Between 2006 and 2008, 8,826 individuals were identified as incident RA patients. The overall incidence was 41 per 100,000 (56 for women, 25 for men). The incidence increased with age and peaked in the 70-79 years age group for both women and men. The age- and sex-standardized incidences were lower in densely populated areas and in individuals with high educational level. No geographic trends were noted. More liberal and strict definitions of RA only altered the observed incidence by approximately 14%.The overall nationwide register-based incidence of RA was robust across different case definitions. In a country with universal access to care, RA displayed demographic and socioeconomic, but no geographic, variations in incidence, and peaks at an older age than most commonly reported, with no difference in peak age at RA onset between sexes.
Reply. Arthritis and rheumatism Simard, J. F., Neovius, M., Askling, J. 2013; 65 (6): 1671-1672
Increased risk of arthropathies and joint replacement surgery in patients with genetic hemochromatosis: a study of 3,531 patients and their 11,794 first-degree relatives. Arthritis care & research Elmberg, M., Hultcrantz, R., Simard, J. F., Carlsson, A., Askling, J. 2013; 65 (5): 678-685
Genetic hemochromatosis (GH) is an autosomal recessive disease in individuals of Northern and Western European descent. Heterozygosity for the C282Y mutation is common (6-20%). Arthropathy is one of the few complications of GH suggested not to be associated with iron body stores; synovial iron deposition remains in iron-depleted patients. Previous studies suggest an elevated prevalence of clinical and radiographic signs of arthropathy in patients with GH, and 2 smaller studies suggest a possibly elevated risk of joint replacement surgery, but more mixed results are shown regarding risks with HFE genotype. We therefore assessed the risks of arthropathy and joint replacement surgery in patients with GH and in their first-degree relatives (FDRs).We performed a population-based cohort study of 3,531 patients with GH and of their 11,794 FDRs (assumed to be heterozygous for the C282Y mutation) using nationwide Swedish population-based health and census registers. Hazard ratios (HRs) of arthropathies and joint replacement surgeries among patients and their FDRs (versus the general population) were assessed using Cox regression.Between 1997 and 2005, 406 of 3,531 patients were reported/hospitalized with any noninfectious arthropathies, including osteoarthritis, corresponding to an HR of 2.38 (95% confidence interval [95% CI] 2.14-2.64). Patients were also at increased risk of hip replacement (HR 2.77, 95% CI 2.27-3.38) and knee replacement (HR 2.14, 95% CI 1.58-2.88) surgery. Among the 11,794 FDRs (patients excluded), we found no increased risk of any of the joint morbidities.Patients with GH, but not their FDRs, are at increased risk of arthropathies, including the need for joint replacement surgery.
Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden BRITISH MEDICAL JOURNAL Raaschou, P., Simard, J. F., Holmqvist, M., Askling, J. 2013; 346
To investigate the potential association between tumour necrosis factor (TNF) inhibitor treatment and malignant melanomas in rheumatoid arthritis, melanoma risks in rheumatoid arthritis patients not treated with biological drugs, and risk of all site cancer with TNF inhibitors as used in rheumatoid arthritis.Population based cohort study.Prospectively recorded data from national clinical, health, and demographic registers in Sweden 2001-10. Patients with rheumatoid arthritis treated (n = 10,878) or not (n = 42,198) with TNF inhibitors and matched general population comparators (n = 162,743).The primary outcome was first invasive melanoma in people without any history of invasive cancer of any type. Hazard ratios were estimated using Cox regression, comparing non-biological drug treated rheumatoid arthritis patients with the general population comparator and TNF inhibitor treated rheumatoid arthritis patients with those not treated with biological drugs. Secondary outcomes included in situ melanomas, second primary melanomas, and all site cancer.113 first invasive melanomas occurred in rheumatoid arthritis patients not treated with biological drugs, and 393 occurred in the general population comparator cohort. Rheumatoid arthritis patients not treated with biological drugs were not at significantly increased risk of melanoma compared with the general population (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5). 38 first invasive melanomas occurred in rheumatoid arthritis patients treated with TNF inhibitors; these patients had an increased risk of melanoma compared with rheumatoid arthritis patients not treated with biological drugs (hazard ratio 1.5, 1.0 to 2.2; 20 additional cases per 100,000 person years). The risk of a second primary melanoma was non-significantly increased (hazard ratio 3.2, 0.8 to 13.1; n=3 v 10) in rheumatoid arthritis patients treated with TNF inhibitors compared with those not treated with biological drugs.Overall, patients with rheumatoid arthritis who have not been treated with biological drugs are not at increased risk of invasive melanoma compared with the general population. Rheumatoid arthritis patients selected for TNF inhibitor treatment are not at increased overall risk for cancer but have a 50% increased relative risk of invasive melanoma. Given the small increase in absolute risk, these finding may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons.
View details for DOI 10.1136/bmj.f1939
Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Leval, A., Herweijer, E., Ploner, A., Eloranta, S., Simard, J. F., Dillner, J., Young, C., Netterlid, E., Sparen, P., Arnheim-Dahlstrom, L. 2013; 105 (7): 469-474
Incidence of condyloma, or genital warts (GW), is the earliest possible disease outcome to measure when assessing the effectiveness of human papillomavirus (HPV) vaccination strategies. Efficacy trials that follow prespecified inclusion and exclusion criteria may not be fully generalizable to real-life HPV vaccination programs, which target a broader segment of the population. We assessed GW incidence after on-demand vaccination with quadrivalent HPV vaccine using individual-level data from the entire Swedish population.An open cohort of girls and women aged 10 to 44 years living in Sweden between 2006 and 2010 (N > 2.2 million) was linked to multiple population registers to identify incident GW in relation to HPV vaccination. For vaccine effectiveness, incidence rate ratios of GW were estimated using time-to-event analyses with adjustment for attained age and parental education level, stratifying on age at first vaccination.A total of 124 000 girls and women were vaccinated between 2006 and 2010. Girls and women with at least one university-educated parent were 15 times more likely to be vaccinated before age 20 years than girls and women whose parents did not complete high school (relative risk ratio = 15.45, 95% confidence interval [CI] = 14.65 to 16.30). Among those aged older than 20 years, GW rates declined among the unvaccinated, suggesting that HPV vaccines were preferentially used by women at high risk of GW. Vaccination effectiveness was 76% (95% CI = 73% to 79%) among those who received three doses of the vaccine with their first dose before age 20 years. Vaccine effectiveness was highest in girls vaccinated before age 14 years (effectiveness = 93%, 95% CI = 73% to 98%).Young age at first vaccination is imperative for maximizing quadrivalent HPV vaccine effectiveness.
View details for DOI 10.1093/jnci/djt032
Mortality Rates in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors Drug-Specific Comparisons in the Swedish Biologics Register ARTHRITIS AND RHEUMATISM Simard, J. F., Neovius, M., Askling, J. 2012; 64 (11): 3502-3510
To determine whether the differences in the modes of action and safety profiles of individual tumor necrosis factor inhibitors (TNFi) translate into differential mortality risks, as investigated in etanercept, infliximab, and adalimumab.Data on patients with rheumatoid arthritis (RA) identified in the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]) in whom first-ever treatment with a biologic agent (etanercept [n = 2,686], infliximab [n = 2,027], or adalimumab [n = 1,609]) was initiated between 2003 and 2008 were linked to national Swedish registers to get information on deaths from any cause, demographic features, RA characteristics, comorbid conditions, and concurrent treatment at the start of TNFi treatment. Hazard ratios (HRs) were modeled using multivariable adjusted and weighted Cox models.During 19,118 person-years of followup, 211 patients died (3.3%; 1.1 deaths per 100 person-years); 85% of the deaths occurred among patients who had been exposed to only one TNFi. We found no statistically significant difference in overall mortality rates across the exposure groups, regardless of adjustment and modeling approach (for infliximab versus etanercept, HR 1.1 [95% confidence interval (95% CI) 0.7-1.7], and for adalimumab versus etanercept, HR 1.3 [95% CI 0.9-2.0]).Overall, we noted no statistically significant difference in mortality rates between the 3 TNF inhibitors under study. Further studies need to examine whether certain subsets of patients are at increased risk of death with specific TNFi.
Increased Risk of Systemic Lupus Erythematosus in 29,000 Patients with Biopsy-verified Celiac Disease JOURNAL OF RHEUMATOLOGY Ludvigsson, J. F., Rubio-tapia, A., Chowdhary, V., Murray, J. A., Simard, J. F. 2012; 39 (10): 1964-1970
To investigate a possible association between celiac disease (CD) and systemic lupus erythematosus (SLE). Case series have indicated a possible association, but population-based studies are lacking.We compared the risk of SLE in 29,048 individuals with biopsy-verified CD (villous atrophy, Marsh 3) from Sweden's 28 pathology departments with that in 144,352 matched individuals from the general population identified through the Swedish Total Population Register. SLE was defined as having at least 2 records of SLE in the Swedish Patient Register. We used Cox regression to estimate hazard ratios (HR) for SLE.During followup, 54 individuals with CD had an incident SLE. This corresponded to an HR of 3.49 (95% CI 2.48-4.90), with an absolute risk of 17/100,000 person-years and an excess risk of 12/100,000. Beyond 5 years of followup, the HR for SLE was 2.54 (95% CI 1.57-4.10). While SLE was predominantly female, we found similar risk estimates in men and women. When we restricted our outcome to individuals who also had a dispensation for a medication used in SLE, the HR was 2.43 (95% CI 1.22-4.87). The HR for having 2 records of SLE diagnoses, out of which at least 1 had occurred in a department of rheumatology, nephrology/dialysis, internal medicine, or pediatrics, was 2.87 (95% CI 1.97-4.17).Individuals with CD were at a 3-fold increased risk of SLE compared to the general population. Although this excess risk remained more than 5 years after CD diagnosis, absolute risks were low.
Incidence of Genital Warts in Sweden Before and After Quadrivalent Human Papillomavirus Vaccine Availability JOURNAL OF INFECTIOUS DISEASES Leval, A., Herweijer, E., Arnheim-Dahlstrom, L., Walum, H., Frans, E., Sparen, P., Simard, J. F. 2012; 206 (6): 860-866
More than 90% of genital warts (GW) cases are caused by human papillomavirus (HPV) types 6 and 11. The introduction of HPV vaccines necessitates the estimation of the population-based incidence of GW immediately before and after vaccination uptake.Incidence proportions were calculated using the entire population aged 10–44 years living in Sweden during 2006–2010. The Prescribed Drug Register and the National Patient Register were used to define GW episodes. Time trends were estimated using Poisson regression.In 2010, age-stratified incidence proportions of GW were highest for 20-year-old women (956 cases/100 000), while the incidence proportion among males was greatest at the slightly older age of 24 years (1137 cases/100 000). Crude rates were marginally higher among males than among females during 2006–2007 and appeared to later diverge. Between 2008 and 2010, the overall incidence appeared to increase among males, and the incidence among females declined. Females aged 17 and 18 years had a >25% decline in GW rates between 2006 and 2010, with significant decreases through the age of 25 years.This study provides a reasonable estimation of the incidence of GW in the Swedish population by use of register data, with results comparable to those from previous smaller studies. There was a downward trend of GW incidence among younger females between 2006 and 2010.
View details for DOI 10.1093/infdis/jis405
Rheumatoid factor positivity in the general population BRITISH MEDICAL JOURNAL Simard, J. F., Holmqvist, M. 2012; 345
View details for DOI 10.1136/bmj.e5841
Risk of ischaemic heart disease and cardiomyopathy in patients with haemochromatosis and in their first-degree relatives: a nationwide, population-based study JOURNAL OF INTERNAL MEDICINE Elmberg, M., Hultcrantz, R., Simard, J. F., Stal, P., Pehrsson, K., Askling, J. 2012; 272 (1): 45-54
Iron-loaded macrophages increase atherosclerosis formation. Genetic haemochromatosis (GH) is an autosomal recessive disease characterized by iron overload, for example in the myocardium, but the reticuloendothelial system is depleted of iron. In contrast to the elevated risk of cardiomyopathy in GH, the risk of ischaemic heart disease (IHD) may therefore not be increased. Little is known of these risks among heterozygotes also being first-degree relatives (FDRs), thus sharing other factors for phenotypic expression of GH.To assess the risks of IHD and cardiomyopathy among haemochromatosis patients and their FDRs.Population-based cohort study.A total of 3531 haemochromatosis patients and 11 794 FDRs were identified using nationwide, population-based health and census registers. Matched (1:10) population controls were randomly selected. Individuals with a record of IHD and cardiomyopathy during 1997-2005 were identified through linkage with the National Patient Register. Relative risks were estimated using Cox proportional hazard regression.Of the 3531 patients, 259 were diagnosed with IHD compared with 3077 of the 37 369 controls [hazard ratio (HR) = 1.17; 95% CI, 1.03-1.33]. Based on 30 patients versus 115 controls, the HR for cardiomyopathy was 3.21 (95% CI, 2.15-4.81). Of 11 794 FDRs of haemochromatosis patients, 582 were registered with IHD compared with 6197 among FDRs of controls (HR = 1.05; 95% CI, 0.97-1.15). Based on 28 FDRs of patients versus 291 FDRs of controls registered with cardiomyopathy, the HR for cardiomyopathy was 1.06 (95% CI, 0.72-1.56).In patients with haemochromatosis, the increased risk of cardiomyopathy is much more pronounced than that of IHD, which is barely elevated. FDRs of haemochromatosis patients are not at increased risk of cardiomyopathy or IHD.
Is there a sex bias in prescribing anti-tumour necrosis factor medications to patients with rheumatoid arthritis? A nation-wide cross-sectional study ANNALS OF THE RHEUMATIC DISEASES Arkema, E. V., Neovius, M., Joelsson, J. K., Simard, J. F., Van Vollenhoven, R. F. 2012; 71 (7): 1203-1206
To determine whether men and women with rheumatoid arthritis are prescribed anti-tumour necrosis factor (anti-TNF) treatment at different levels of disease activity.Data from the Swedish national biologics registry ARTIS were used to analyse characteristics of patients' disease at the start of the first anti-TNF treatment. Means for men and women were compared using t-tests, and non-normally distributed covariates were compared using the Wilcoxon rank-sum test. Linear regression models, adjusted for age and calendar year, were used to investigate the association between sex and each disease activity measurement.Women were younger and had longer disease duration at treatment start than men. Tender joint count, erythrocyte sedimentation rate, patient's global assessment, patient-reported pain and health assessment questionnaire scores were significantly higher in women, whereas men had a higher level of C-reactive protein (p<0.05 for all comparisons). Swollen joint count and physician's global assessment did not differ by sex.For women with rheumatoid arthritis, treatment with anti-TNF therapy was initiated at a higher level of subjective disease activity than for men, but at the same level of physician-reported disease activity. These data imply that patients' subjectively experienced disease activity may be discounted in the treatment decision.
TNF-a Antagonist and Infection in Rheumatoid Arthritis. Open journal of rheumatology and autoimmune diseases Simard, J. F., Mittleman, M. A., Shadick, N. A., Karlson, E. W. 2012; 2 (2): 14-20
Anti-TNF treatment may increase infection risk, although this has been difficult to study because the timing of anti-TNF treatment is driven by disease activity, which may influence infection susceptibility leading to confounding that varies over time. We evaluated the association between anti-TNF initiation in rheumatoid arthritis (RA) patients on disease modifying anti-rheumatic drugs (DMARD) and infection using multiple approaches adjusting for time-varying confounding.383 anti-TNF-naïve RA patients on ≥1 non-biologic-DMARD at enrollment from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) were followed up to two years. Pooled logistic regressions estimated the association between anti-TNF and infection by including time-varying covariates in the adjusted models and inverse probability treatment weighting (IPTW).Adjustment for time-varying disease activity and other suspected confounders yielded non-statistically significant positive associations between anti-TNF start and infection regardless of analytic approach (RRmvar_adj = 2.1, 95% CI: 0.8 - 5.8).Incorporating changing clinical status, and treatment indications and consequences, yielded consistently (though not significantly) elevated relative risks of infection associated with anti-TNF initiation. Due to limited statistical power, we cannot draw firm conclusions. However, we have illustrated multiple approaches adjusting for potential time-varying confounding in longitudinal studies and hope to replicate the approaches in larger studies.
Treatment with tumor necrosis factor inhibitors and the risk of acute coronary syndromes in early rheumatoid arthritis ARTHRITIS AND RHEUMATISM Ljung, L., Simard, J. F., Jacobsson, L., Rantapaa-Dahlqvist, S., Askling, J. 2012; 64 (1): 42-52
Rheumatoid arthritis (RA) is associated with an increased risk of ischemic heart disease, in both early and established RA. Data on the risk of ischemic heart disease in relation to therapy with tumor necrosis factor (TNF) antagonists (anti-TNF) are conflicting in patients with established RA and essentially lacking in those with early RA. In established RA, the risk of myocardial infarction has been linked to the response to anti-TNF therapies. The aim of this study was to determine the risk of acute coronary syndromes (ACS) in patients with early RA in relation to treatment with, and response to, anti-TNF.A cohort consisting of patients in whom RA was diagnosed between 1999 and 2007 was identified from the Swedish Rheumatology Register (n=6,000), from which information on disease activity and pharmacologic treatments was extracted. In a cohort study, the risk of first occurrence of an ACS was compared between patients treated with anti-TNF and those without exposure to anti-TNF, using hazard ratios (HRs). In a nested case-control study, the relationship between response to anti-TNF according to the European League Against Rheumatism (EULAR) response criteria and the risk of ACS was investigated.In the cohort study, treatment with anti-TNF was not related to any statistically significant alteration in the risk of ACS (HR 0.80, 95% confidence interval [95% CI] 0.52-1.24). In the nested case-control study, a good or moderate EULAR treatment response at 3 months and at 6 months was not associated with a risk of ACS (odds ratio [OR] 1.7, 95% CI 0.5-5.1 and OR 1.5, 95% CI 0.3-6.9, respectively), when adjusted for disease activity before treatment start.In this study of patients treated with anti-TNF within the first years of RA, neither treatment with, nor response to, anti-TNF therapy could be linked to any statistically significant decrease in the risk of ACS.
Risk factors for cardiovascular mortality in patients with systemic lupus erythematosus, a prospective cohort study ARTHRITIS RESEARCH & THERAPY Gustafsson, J. T., Simard, J. F., Gunnarsson, I., Elvin, K., Lundberg, I. E., Hansson, L., Larsson, A., Svenungsson, E. 2012; 14 (2)
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Cardiovascular disease (CVD) is common and a major cause of mortality. Studies on cardiovascular morbidity are abundant, whereas mortality studies focusing on cardiovascular outcomes are scarce. The aim of this study was to investigate causes of death and baseline predictors of overall (OM), non-vascular (N-VM), and specifically cardiovascular (CVM) mortality in SLE, and to evaluate systematic coronary risk evaluation (SCORE).208 SLE patients were included 1995-1999 and followed up after 12 years. Clinical evaluation, CVD risk factors, and biomarkers were recorded at inclusion. Death certificates and autopsy protocols were collected. Causes of death were divided into CVM (ischemic vascular and general atherosclerotic diseases), N-VM and death due to pulmonary hypertension. Predictors of mortality were investigated using multivariable Cox regression. SCORE and standardized mortality ratio (SMR) were calculated.During follow-up 42 patients died at mean age of 62 years. SMR 2.4 (CI 1.7-3.0). 48% of deaths were caused by CVM. SCORE underestimated CVM but not to a significant level. Age, high cystatin C levels and established arterial disease were the strongest predictors for all- cause mortality. After adjusting for these in multivariable analyses, only smoking among traditional risk factors, and high soluble vascular cell adhesion molecule-1 (sVCAM-1), high sensitivity C-reactive protein (hsCRP), anti-beta2 glycoprotein-1 (abeta2GP1) and any antiphospholipid antibody (aPL) among biomarkers, remained predictive of CVM.With the exception of smoking, traditional risk factors do not capture the main underlying risk factors for CVM in SLE. Rather, cystatin C levels, inflammatory and endothelial markers, and antiphospholipid antibodies (aPL) differentiate patients with favorable versus severe cardiovascular prognosis. Our results suggest that these new biomarkers are useful in evaluating the future risk of cardiovascular mortality in SLE patients.
View details for DOI 10.1186/ar3759
Time Trends in Risk and Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients AMERICAN JOURNAL OF TRANSPLANTATION Fernberg, P., Edgren, G., Adami, J., Ingvar, A., Bellocco, R., Tufveson, G., Hoglund, P., Kinch, A., Simard, J. F., Baecklund, E., Lindelof, B., Pawitan, Y., Smedby, K. E. 2011; 11 (11): 2472-2482
Organ transplantation increases risk of non-Hodgkin lymphoma (NHL), but long-term risk and time trends have seldom been evaluated. Immunosuppressive drug load is an important risk determinant, but the details are unclear. We studied NHL risk in a nationwide Swedish cohort of 11 081 graft recipients transplanted 1970-2008. Relative risks (RRs) were estimated within the cohort and versus the general population by age, sex, follow-up time and calendar period. NHL risk was also assessed by cumulative and average doses of immunosuppressive treatments in a nested case-control design throughout 1997 using conditional logistic regression. We observed 153 NHL cases during 97 853 years of follow-up. Compared with the general population, NHL risk was eightfold increased (RR 7.9; 95% confidence interval [CI] 6.6-9.4), and increased risks persisted after ≥15 years of follow-up among kidney (6.1; 95% CI 3.5-10) and nonkidney recipients (44; 14-103). Among nonkidney recipients, NHL risk was lower in the 2000s compared with the 1990s (0.5; 95% CI 0.3-1.0; p = 0.04). A high average dose of antithymocyte immunoglobulin (ATG) conferred an eightfold increased risk of NHL (OR 8.5; 95% CI 1.9-38). To conclude, posttransplant NHL risk decreased during the last decade among nonkidney recipients, possibly because of a more careful use of ATG, the introduction of new drugs, or both.
Sick leave and disability pension before and after initiation of antirheumatic therapies in clinical practice ANNALS OF THE RHEUMATIC DISEASES Neovius, M., Simard, J. F., Klareskog, L., Askling, J. 2011; 70 (8): 1407-1414
To investigate sick leave and disability pension in rheumatoid arthritis (RA) in relation to the initiation of biological and non-biological antirheumatic therapies in clinical practice.Patients aged 19-60 years initiating non-biological mono (n=2796) or combination disease-modifying antirheumatic drug (DMARD) therapy (n=973), or biological agents (n=4787) were identified in the Swedish Rheumatology Quality Register between 1999 and 2007. Sick leave and disability pension data (1995-2010) were retrieved from national registers.During the year before the start of mono DMARD, combination DMARD and biological treatment, 10%, 12% and 43% of patients received disability pension benefits, respectively. The corresponding combined annual sick leave and disability pension days were 78 (54+25), 132 (105+27) and 190 (79+111). Irrespective of treatment type, initiators were characterised by a history of increasing sick leave and disability pension. Treatment start was associated with a break in this trajectory: sick leave decreased while disability pension increased, resulting in a net stabilisation of total days. Higher levels of days on sick leave and disability pension at treatment start were observed in patients initiating biologics in 1999 (236 days/year) compared with 2007 (150 days/year; p<0.001), but the trajectory thereafter remained largely similar and contrasted markedly with the level in the general population.Sick leave and disability pension increased rapidly before the initiation of antirheumatic therapy, which was associated with a halt but not a reversal of this development. Work ability is a metric of importance for clinical practice, signalling large remaining needs in the RA population, and the need for intervention earlier in the disease process.
View details for DOI 10.1136/ard.2010.144139
Does Cancer That Occurs During or After Anti-Tumor Necrosis Factor Therapy Have a Worse Prognosis? A National Assessment of Overall and Site-Specific Cancer Survival in Rheumatoid Arthritis Patients Treated With Biologic Agents ARTHRITIS AND RHEUMATISM Raaschou, P., Simard, J. F., Neovius, M., Askling, J. 2011; 63 (7): 1812-1822
Tumor necrosis factor (TNF) may affect tumor development and spreading. While data on the incidence of cancer following anti-TNF therapy have been published, the purpose of this study was to examine the clinical presentation and outcome of cancers that develop during or after anti-TNF therapy.By linking data from Swedish clinical registries of rheumatoid arthritis (RA) patients, including Anti-Rheumatic Therapy in Sweden (ARTIS), the Swedish Biologics Register, with nationwide data on hospitalizations and outpatient visits for RA, we assembled a cohort of 78,483 RA patients who were alive in 1999 or who entered the cohort thereafter. Of these, 8,562 patients started therapy with a biologic agent (98% started an anti-TNF) during the period from January 1, 1999 to December 31, 2007. Linkage to the Swedish Cancer Register and other registers identified first primary cancers occurring during 1999-2007 as well as post-cancer survival through March 31, 2009. Through this linkage, we identified 314 cancers in patients who were undergoing, or had a history of, treatment with biologic agents and 4,650 cancers in patients who were biologics-naive at the time of cancer diagnosis. The distributions of tumor stage among the biologics-exposed and the biologics-naive patients were compared. The relative risk of death among the biologics-exposed versus the 586 matched biologics-naive cancer cases were assessed by Cox regression analyses. Through chart review in a defined subset, we gathered additional clinical information and validated the diagnoses.For all cancers combined, the distribution of cancer stages at the time of cancer diagnosis was largely similar between those in the biologics-exposed and the matched biologics-naive groups. Based on the total of 113 deaths among those with cancer in the biologics-exposed group versus the 256 deaths among those with cancer in the biologics-naive group, the relative risk of death following cancer associated with exposure to anti-TNF was 1.1 (95% confidence interval 0.8-1.6).During routine care, cancers that occur following anti-TNF therapy are not characterized by any markedly altered stage at presentation or by altered post-cancer survival rates.
How large are the productivity losses in contemporary patients with RA, and how soon in relation to diagnosis do they develop? ANNALS OF THE RHEUMATIC DISEASES Neovius, M., Simard, J. F., Askling, J. 2011; 70 (6): 1010-1015
To estimate the sick leave and disability pension trajectory in patients diagnosed with early rheumatoid arthritis (RA) 1999-2007, and in prevalent patients in 2007.Individuals aged 19-59 years diagnosed with early RA were identified in the Swedish Rheumatology Quality Register (1999-2007; n=3029; 47 years; 73% women). Additionally, prevalent patients in 2007 were identified in the National Patient Register (n=25,922; 52 years; 73% women). For each patient, five age-, sex-, education- and county-matched general population comparators were sampled. Sick leave and disability pension days were retrieved from national registers.Sick leave and disability pension increased from a mean 43 to 77 days/year from 2 to 1 years before RA diagnosis. A further increase to 147 days/year was observed the next year, followed by a rebound to 116 days/year 4 years after diagnosis. During the 4 years following diagnosis, sick leave decreased from a mean 118 to 35 and disability pension increased from 29 to 81 days/year. In the prevalent RA population, patients had a mean 158 annual days of sick leave and disability pension compared to 71 in comparators. Large variations existed across age, sex and education level, but RA patients had consistently higher levels. In 2007, the costs associated with sick leave and disability pension were €16,000 per patient with €9,000 attributable to RA.Despite better drugs and improved treatment strategies, data from contemporary patients with early and established RA continue to indicate large unmet needs.
Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden ANNALS OF THE RHEUMATIC DISEASES Neovius, M., Simard, J. F., Askling, J. 2011; 70 (4): 624-629
To provide Swedish nationwide data on the prevalence of rheumatoid arthritis (RA), including variations by age, sex, geography, demography and education level, and assess antirheumatic treatment penetration.Patients ≥16 years assigned an RA diagnosis were identified from inpatient (n=96 560; 1964-2007) and specialist outpatient care (n=56 336; 2001-2007) in the Swedish National Patient Register, and the Swedish Rheumatology Quality Register (n=21 242; 1995-2007). Data on prescriptions, demography, vital status and educational level were retrieved from national registers.A total of 58 102 individuals (mean age 66 years; 73% women) assigned an RA diagnosis were alive in Sweden in 2008, corresponding to a cumulative prevalence of 0.77% (women 1.11%, men 0.43%). The 2001-2007 period prevalence was 0.70%. Restriction to patients with ≥2 visits or diagnosis from a rheumatologist/internist reduced the overall cumulative prevalence to 0.68%. Whereas urban/rural differences (crude 0.65-1.00%) were explained by age differences, the age/sex-adjusted prevalence remained higher in patients with ≤9 years education (0.86%) than for those with 10-12 years (0.82%) and >12 years (0.65%). Treatment exposures (76% any disease-modifying antirheumatic drugs (DMARDs) or steroids, 64% any DMARD, 15% biological agents) varied with age; use of biological agents decreased from 22% in 16-59 years olds to 3% in ≥80 years olds. Any DMARD use correspondingly decreased from 71% to 43%. Applying age cut-off points from previous northern European and North American prevalence studies reduced or eliminated between-study differences.This nationwide approach yielded a prevalence of RA similar to previous regional assessments. While displaying only modest geographical variation and no urban/rural gradient, prevalence was associated with educational level. Although most patients received antirheumatic drugs, age was a strong treatment determinant.
Generalisability of clinical registers used for drug safety and comparative effectiveness research: coverage of the Swedish Biologics Register ANNALS OF THE RHEUMATIC DISEASES Neovius, M., Simard, J. F., Sundstrom, A., Jacobsson, L., Geborek, P., Saxne, T., FELTELIUS, N., Klareskog, L., Askling, J. 2011; 70 (3): 516-519
To determine coverage and generalisability of data in the Swedish Biologics Register ARTIS.Patients with adult onset rheumatoid arthritis (RA) were identified in the National Patient Register and the Swedish Rheumatology Quality Register, including the ARTIS cohort of patients exposed to biological agents. Exposure to etanercept and adalimumab between 2006 and 2008 was determined by register linkage to the Prescribed Drug Register which contains patient-level data on >99% of all etanercept and adalimumab use in Sweden.Of 62 897 patients with RA, 6510 had received treatment with etanercept or adalimumab according to the Prescribed Drug Register. Of these, 5673 were also registered in ARTIS, resulting in a national coverage of 87%. The regional variation was small with >85% coverage in 18 of 21 counties. In multivariable analysis, ARTIS-registered and non-registered patients did not differ by age (p=0.62), sex (p=0.84) or education level (p=0.24).Nationwide drug dispensing and demographic data may function as quality metrics for coverage and generalisability assessments. Using such data, the coverage of ARTIS was estimated at 87% with no indications of compromised external generalisability regarding demography.
Ten years with biologics: to whom do data on effectiveness and safety apply? RHEUMATOLOGY Simard, J. F., Arkema, E. V., Sundstrom, A., Geborek, P., Saxne, T., Baecklund, E., Coster, L., Dackhammar, C., Jacobsson, L., Feltelius, N., Lindblad, S., Rantapaa-Dahlqvist, S., Klareskog, L., Van Vollenhoven, R. F., Neovius, M., Askling, J. 2011; 50 (1): 204-213
During the past decade, the position of biologics in the therapeutic armamentarium, the number of approved indications and the number of available biologics have changed. Available data on (long-term) safety might thus pertain to patient populations not comparable with contemporary patients. The aim of this study was to assess the extent to which contemporary patients who start or switch biologic therapies are comparable with those patients who gave rise to the currently available data on effectiveness and safety.We identified all adult patients with RA (n=9612), PsA (n=1417) and other SpA (n=1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation.Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite <50% drug retention at 5 years, most patients remained exposed to some biologic.The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.
View details for DOI 10.1093/rheumatology/keq326
Pediatric Organ Transplantation and Risk of Premalignant and Malignant Tumors in Sweden AMERICAN JOURNAL OF TRANSPLANTATION Simard, J. F., Baecklund, E., Kinch, A., Brattstrom, C., Ingvar, A., Molin, D., Adami, J., Fernberge, P., Wilczek, H., Ekbom, A., Smedby, K. E. 2011; 11 (1): 146-151
Increased cancer risks are well documented in adult organ transplant recipients. However, the spectrum of malignancies and risk in the pediatric organ transplant population are less well described. We identified all solid organ transplanted patients aged <18 in Sweden between 1970-2007 (n = 536) in the National Patient Register and linked to the Cancer Register. Nationwide rates were used to calculate standardized incidence rate ratios and 95% CI estimating the association between transplant and cancer during maximum 36 years of follow-up. Nearly 7% of pediatric solid organ transplant recipients developed a premalignant or malignant tumor during follow-up. Transplantation was associated with an increased risk of any cancer (n = 24, SIR = 12.5, 95% CI: 8.0-18.6): non-Hodgkin lymphoma (NHL) (n = 13, SIR = 127, 95% CI: 68-217), renal cell (n = 3, SIR = 105, 95% CI: 22-307), vulva/vagina (n = 3, SIR = 665, 95% CI: 137-1934) and nonmelanoma skin cancers (n = 2, SIR = 64.7, 95% CI: 7.8-233.8). NHL typically appeared during childhood, while other tumors were diagnosed during adulthood. Apart from short-term attention toward the potential occurrence of NHL, our results suggest cancer surveillance into adulthood with special attention to skin, kidneys and the female genitalia.
Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009 SCANDINAVIAN JOURNAL OF RHEUMATOLOGY Neovius, M., Sundstrom, A., Simard, J. F., Wettermark, B., Cars, T., FELTELIUS, N., Askling, J., Klareskog, L. 2011; 40 (1): 8-15
To measure small-area variations in sales per capita of tumour necrosis factor (TNF) inhibitors.For 2000-2009, sales data on etanercept, infliximab, and adalimumab were retrieved from the Swedish National Corporation of Pharmacies, which keeps data on drugs dispensed in ambulatory care and hospitals. As points of reference, data were retrieved on all drugs, non-biologic treatments for chronic inflammatory disorders (sulfasalazine, methotrexate, azathioprine), and for a biologic used in a different therapeutic area (trastuzumab). As a corollary measure to sales per capita, penetration of biologics in the rheumatoid arthritis (RA) population was calculated using nationwide registers. Small areas were defined as the 21 counties of Sweden.From 2000 to 2009, annual TNF inhibitor sales increased 9-fold from 195 to 1779 million SEK (0.7-5.0% of total drug expenditure). The county variation in sales per capita, initially 6.2-fold (coefficient of variation 42%), decreased to 2.3-fold in 2009 (24%). During the same period, total drug expenditure per capita remained at a 1.2-fold county variation (4-6%). Sales per capita variations of non-biologic treatments against chronic inflammatory diseases ranged from 1.5 to 1.8 (12-16%). For trastuzumab, a 3.2-fold variation (30%) was observed in 2009. At the patient level, there was a 2-fold county variation (from 10% to 21%) in biologic penetration in RA. County-specific sales per capita were associated with mean RA duration (r = -0.52, p = 0.015) and C-reactive protein at treatment initiation (r = -0.49, p = 0.025), while pain was borderline significant (r = -0.43, p = 0.055).Despite universal access to treatment, substantial but decreasing small-area variations were observed. Although geographic variations are anticipated initially, their persistence calls for investigation of patient equity and treatment appropriateness as counties seem to have different initiation thresholds.
View details for DOI 10.3109/03009742.2010.493895
Detection and evaluation of a drug safety signal concerning pancreatic cancer: lessons from a joint approach of three European biologics registers RHEUMATOLOGY Strangfeld, A., Hyrich, K., Askling, J., Arkema, E., Davies, R., Listing, J., Neovius, M., Simard, J., Symmons, D., Watson, K., Zink, A. 2011; 50 (1): 146-151
A high incidence of pancreatic cancer (PCa) in patients exposed to was observed in the German biologics register. To evaluate this possible safety signal, a concerted analysis with the national biologics registers in the UK and Sweden was performed.Patients with enrolled in the British Society of Rheumatology Biologics Register (BSRBR), the Swedish Rheumatology Register (SRR) or the German Biologics Register [Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT)] were analysed. The patients were exposed to biologic or conventional DMARDs. Outcomes were obtained from physician reports, health authorities and via linkage to national cancer and death registers. Age- and gender-standardized incidence ratios (SIRs) of PCa were calculated based on the expected rates available from the individual national cancer registers.Data from 5126 (Germany), 16 930 (UK) and 19 351 (Sweden) RA patients were available for the analysis. The highly discrepant prescription rates of LEF in the respective countries resulted in 11 343 (Germany), 30 787 (UK) and 2518 (S) patient-years of exposure to LEF. Compared with the general population, the incidence of PCa in patients ever exposed to LEF corresponded to a SIR of 3.1 (95% CI 1.3, 6.5) in Germany, 1.05 (95% CI 0.5, 2.1) in the UK and 1.8 (95% CI 0.1, 10.2) in Sweden.The results of the replication analyses do not support the hypothesis of an increased risk of PCa in patients exposed to treatment with LEF. However, they do not completely rule out concerns, and therefore further verification in other data sets is recommended.
Juvenile Idiopathic Arthritis and Risk of Cancer A Nationwide Cohort Study ARTHRITIS AND RHEUMATISM Simard, J. F., Neovius, M., Hagelberg, S., Askling, J. 2010; 62 (12): 3776-3782
Reports of therapy-related adverse events suggest an elevated rate of malignancy in patients with juvenile idiopathic arthritis (JIA) treated with biologic therapies. However, the scarcity of data on the underlying risk of malignancy in JIA hampers interpretation of these signals. Therefore, the aim of this study was to determine the risk of cancer in patients with JIA as compared with that in the general population.Through linkage with a national database, the Swedish Patient Register (comprising inpatient discharges in 1969-2007 and specialist outpatient visits in 2001-2007 in Sweden), a national JIA cohort (n = 9,027) was identified, and each JIA case was matched with 5 general population comparators. Using data from the Swedish Cancer, Census, Death, and Biologics Registers, the occurrence of cancer, vital status, and start of a biologic therapy were identified. The relative risk (RR) of first occurrence of a primary cancer in patients who had not been treated with biologics (biologics-naive patients with JIA) was estimated using Poisson regression, stratified a priori by year of earliest identification of JIA (before 1987 versus 1987 and thereafter). In sensitivity analyses, the data were followed up to 1999, when biologics first became available.In this biologics-naive JIA cohort, 60 malignancies were observed during 131,144 person-years of followup, compared with 266 cancers observed during 661,758 person-years in the general population comparator (0.46 cases/1,000 person-years versus 0.40 cases/1,000 person-years; RR 1.1, 95% confidence interval [95% CI] 0.9-1.5). Patients with JIA identified before 1987 were not at increased risk of cancer, whereas JIA identified in 1987 and thereafter was significantly associated with incident lymphoproliferative malignancies (RR 4.2, 95% CI 1.7-10.7) and cancers overall (RR 2.3, 95% CI 1.2-4.4). Sensitivity analyses did not reveal any ready explanation for this heterogeneity.Although absolute risks were low, an elevated risk of malignancy was observed among biologics-naive patients in whom the diagnosis of JIA was made in the past 20 years, which may have implications for the interpretation of cancer signals in patients with JIA treated with newer therapies.
Validity of self-report of infections in a longitudinal cohort of patients with rheumatoid arthritis differs by source of report and infection severity JOURNAL OF CLINICAL EPIDEMIOLOGY Simard, J. F., Stoll, M. L., Shadick, N. A., Karlson, E. W., Solomon, D. H. 2010; 63 (12): 1358-1362
We evaluated and compared the validity of patients' and rheumatologists' reports of infection with those confirmed by medical record review.Reports of infections in 961 patients with rheumatoid arthritis from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) were included over a 2-year period. BRASS is a longitudinal prospective cohort that collects detailed questionnaire data from patients semiannually and their treating rheumatologists every year.Rheumatologist report of infection was more likely to be confirmed by medical record review than patient self-report (57.1% vs. 34.3% for definite or possible infections). Confirmation rates varied based on whether the participant received her primary care from the same network of health care providers. For participants with primary care "out of network," between 7.0% and 23.1% of patient or rheumatologist reports were confirmed by medical record review vs. between 16.1% and 41.7% for those with primary care "in network."The present study shows that relying strictly on patient or rheumatologist report of infection for a confirmed endpoint is not ideal but useful in case finding. The confirmation rate is affected by a number of factors including severity and definition of the infection and limited by data availability.
View details for DOI 10.1016/j.jclinepi.2010.01.014
A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus ANNALS OF THE RHEUMATIC DISEASES Svenungsson, E., Gustafsson, J., Leonard, D., Sandling, J., Gunnarsson, I., Nordmark, G., Jonsen, A., Bengtsson, A. A., Sturfelt, G., Rantapaa-Dahlqvist, S., Elvin, K., Sundin, U., Garnier, S., Simard, J. F., Sigurdsson, S., Padyukov, L., Syvanen, A., Ronnblom, L. 2010; 69 (5): 834-840
To investigate whether the risk allele for systemic lupus erythematosus (SLE) in the signal transducer and activator of transcription factor 4 (STAT4) gene, defined by the single nucleotide polymorphism (SNP) rs10181656(G), is associated with vascular events and/or presence of prothrombotic anti-phospholipid antibodies (aPL) in patients with SLE.Two independent groups of unrelated patients with SLE of Swedish ethnicity (n=424 and 154) were genotyped, and occurrence of previous manifestations of ischaemic heart disease (IHD), ischaemic cerebrovascular disease (ICVD) and venous thromboembolic events (VTE) was tabulated. aPL values were measured by ELISA. Matched controls (n=492 and 194) were genotyped.The STAT4 risk allele was more frequent in patients with SLE with previous arterial events (combined OR (OR(c))=1.5, 95% CI 1.1 to 2.0) compared to patients without such events. The association was mainly attributable to an accumulation of the risk allele among patients with ICVD (OR(c)=2.3, CI 1.6 to 3.3). There was no association with IHD or VTE. The presence of two or more aPLs was associated with the risk allele (OR(c)=1.6, 95% CI 1.2 to 2.0). In multivariable-adjusted logistic regression analyses treatment for hypertension, at least one STAT4 risk allele, older age, IgG anti-cardiolipin antibodies and longer SLE duration remained independently associated with previous ICVD (p
Early Life Factors and Adult-onset Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Simard, J. F., Costenbader, K. H., Hernan, M. A., Liang, M. H., Mittleman, M. A., Karlson, E. W. 2010; 37 (1): 32-37
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 2 large prospective cohorts.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 and being breastfed and its duration, adjusting for potential confounders. Random effects metaanalytic methods were used to compute combined estimates from the 2 cohorts.We found no statistically significant association between preterm birth and incident RA [relative risk (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 duration of breastfeeding.In these cohorts of women, neither being preterm birth nor being breastfed was associated with the onset of RA.
TNF alpha Inhibitors May Improve Asthma Symptoms: A Case Series of 12 Patients With Rheumatoid Arthritis and Asthma JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Stoll, M. L., Solomon, D. H., Batra, K. L., Simard, J. F., Karlson, E. W., Dellaripa, P. F., Weinblatt, M. E., Glass, R., Shadick, N. A. 2009; 15 (4): 198-200
View details for DOI 10.1097/RHU.0b013e3181a7ace9
Is birthweight associated with risk of rheumatoid arthritis? Data from a large cohort study ANNALS OF THE RHEUMATIC DISEASES Mandl, L. A., Costenbader, K. H., Simard, J. F., Karlson, E. W. 2009; 68 (4): 514-518
The "fetal origins of adult disease" hypothesis suggests the uterine environment can influence the susceptibility of a fetus to future disease. We examine whether the fetal environment, as reflected by birthweight, could modulate an individual's future risk of rheumatoid arthritis (RA).The relationship between birthweight and the risk of incident RA was studied in 87 077 women followed prospectively in the Nurses' Health Study cohort. New cases of RA diagnosed between 1976 and 2002 were confirmed in 619 women. The association between birthweight and the future development of RA was studied in age-adjusted and Cox proportional hazard models adjusting for age and potential confounders, including history of maternal diabetes, childhood socioeconomic status, prematurity, maternal and paternal smoking, as well as additionally adjusting for risk factors for RA including smoking, age at menarche, use of oral contraceptives, use of post-menopausal hormones, total lifetime breastfeeding, and body mass index (BMI) at age 18.In an age-adjusted model, birthweight >4.54 kg vs birthweight 3.2-3.85 kg was associated with a two-fold increased risk of RA (relative risk (RR) = 2.1, 95% CI 1.4 to 3.3). Further adjusting for potential confounders and risk factors did not change this relationship (RR = 2.0, 95% CI 1.3 to 3.0). Findings were similar when we limited cases to those with rheumatoid factor positive RA (RR = 2.1, 95% CI = 1.2 to 3.6).In this large prospective cohort, birthweight >4.54 kg was associated with a two-fold increased risk of adult onset RA, compared with those of average birthweight. Further study of this observation may provide insight into the pathogenesis of RA.
Exposure to maternal smoking and incident SLE in a prospective cohort study LUPUS Simard, J. F., Costenbader, K. H., Liang, M. H., Karlson, E. W., Mittleman, M. A. 2009; 18 (5): 431-435
Current cigarette smoking is a risk factor for SLE, and recent work has demonstrated that early-life smoke exposure was related to the risk of related rheumatic conditions in female children. Therefore, we sought to investigate whether early-life cigarette smoke exposure might be associated with incidence of SLE in adult women. We studied 93,054 Nurses' Health Study (NHS) and 95,554 NHSII participants free of SLE at baseline who provided information on perinatal exposures. By medical record review, 236 incident SLE cases were confirmed (142 NHS and 94 NHSII) among these women using American College of Rheumatology criteria. We used stratified Cox models to estimate the association of smoke exposure with SLE adjusting for race, birth weight, preterm birth and parents' occupation. Combined estimates were computed using random effects meta-analytic techniques. Maternal cigarette smoking did not increase the risk of SLE (relative risk (RR) = 0.9, 95%CI: 0.6 to 1.4) nor did paternal smoking during the participant's childhood (RR = 1.0, 95% CI: 0.8 to 1.3) in combined analyses. Early-life exposure to cigarette smoke due to mothers' or fathers' smoking was not associated with increased risk of adult-onset SLE in women.
Methodologic issues in the validation of putative biomarkers and surrogate endpoints in treatment evaluation for systemic lupus erythematosus. Endocrine, metabolic & immune disorders drug targets Liang, M. H., Simard, J. F., Costenbader, K., Dore, B. T., Ward, M., Fortin, P. R., Illei, G. G., Manzi, S., Mittleman, B., Buyon, J., Gupta, S., Abrahamowicz, M. 2009; 9 (1): 108-112
No new drugs have been approved for the treatment of systemic lupus erythematosus (SLE) by the Food and Drug Administration for the last 30 years. One barrier has been the lack of validated biomarkers and surrogate endpoints. Validation of SLE biomarkers in the past have been methodologically flawed. We put forth a conceptual framework and five critical criterion for validating putative biomarkers and bio-surrogates in this heterogeneous multi-system disease with protean manifestations. Using the example of a putative biomarker for end-stage lupus nephritis, we performed computer simulations for planning a biomarker bio-repository to support the validation process. "Random time window" sampling where a biomarker is obtained in an interval randomly selected from the total follow-up time for that subject creates survival bias. This can be avoided by the "fixed calendar window" design, in which biomarkers are measured within the same, pre-specified period for all cohort members who remain at risk during that period. In lupus nephritis where the incidence rate of end-stage renal disease is relatively low, to accumulate 300 instances of end-stage renal disease, at risk patients would have to be followed for about 5,000 person-years, implying 500 subjects followed, on average, for about 10 years. Increasing the number of biomarker determinations per subject from one to five reduces the required number of subjects by 10-15%, while further increases in the number of observations per subject yielded much smaller gains. The large numbers of subjects required for a bio-repository, makes it essential to maximize the efficiency of study designs and analyses and provides the strongest rationale for collaboration and the use of standardized measures to ensure comparability.
Predictors of the first cardiovascular event in patients with systemic lupus erythematosus - a prospective cohort study ARTHRITIS RESEARCH & THERAPY Gustafsson, J., Gunnarsson, I., Borjesson, O., Pettersson, S., Moller, S., Fei, G., Elvin, K., Simard, J. F., Hansson, L., Lundberg, I. E., Larsson, A., Svenungsson, E. 2009; 11 (6)
Cardiovascular disease (CVD) is a major cause of premature mortality among Systemic lupus erythematosus (SLE) patients. Many studies have measured and evaluated risk factors for premature subclinical atherosclerosis, but few studies are prospective and few have evaluated risk factors for hard endpoints, i.e. clinically important cardiovascular events (CVE). We investigated the impact of traditional and lupus associated risk factors for the first ever CVE in a longitudinal cohort of SLE patients.A total of 182 SLE patients (mean age 43.9 years) selected to be free of CVE were included. Cardiovascular and autoimmune biomarkers were measured on samples collected after overnight fasting at baseline. Clinical information was collected at baseline and at follow up. End point was the first ever CVE (ischemic heart, cerebrovascular or peripheral vascular disease or death due to CVD). Impact of baseline characteristics/biomarkers on the risk of having a first CVE was evaluated with Cox regression.Follow up was 99.5% after a mean time of 8.3 years. Twenty-four patients (13%) had a first CVE. In age-adjusted Cox regression, any positive antiphospholipid antibody (aPL), elevated markers of endothelial activation (von Willebrand factor (vWf), soluble vascular cellular adhesion molecule-1 (sVCAM-1)) and fibrinogen predicted CVEs. Of SLE manifestations, arthritis, pleuritis and previous venous occlusion were positively associated with future CVEs while thrombocytopenia was negatively associated. Among traditional risk factors only age and smoking were significant predictors. In a multivariable Cox regression model age, any positive aPL, vWf and absence of thrombocytopenia were all predictors of the first CVE.In addition to age, positive aPL, biomarkers indicating increased endothelial cell activity/damage, and absence of thrombocytopenia were independent predictors of CVEs in this prospective study. Our results indicate that activation of the endothelium and the coagulation system are important features in SLE related CVD. Furthermore, we observed that the risk of CVEs seems to differ between subgroups of SLE patients.
Perinatal factors and adult-onset lupus 40th Annual Meeting of the Society-for-Epidemiologic-Research Simard, J. F., Karlson, E. W., Costenbader, K. H., Hernan, M. A., Stampfer, M. J., Liang, M. H., Mittleman, M. A. WILEY-LISS. 2008: 1155–61
Some evidence suggests that perinatal factors, including birth weight and breastfeeding, may influence the occurrence of autoimmune rheumatic diseases. However, few studies have investigated these factors in patients with systemic lupus erythematosus (SLE). Therefore, we evaluated the role of birth weight, being breastfed, and preterm birth on the incidence of SLE in participants in the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHSII).We studied 87,411 NHS participants and 98,413 NHSII participants without SLE at baseline who provided information on perinatal exposures. Among these women, during 26 (NHS) and 14 (NHSII) years of followup, 222 incident SLE cases were confirmed (136 NHS and 86 NHSII) by medical record review using American College of Rheumatology criteria. We used stratified Cox models to estimate the association of perinatal factors with SLE, adjusting for race, early passive cigarette smoke exposure, and parents' occupation. A random-effects meta-analysis was used to compute combined estimates across the 2 cohorts.After adjustment for multiple potential confounders, high birth weight (> or =10 pounds) was associated with increased rates of SLE compared with normal birth weight (7-8.5 pounds; rate ratio [RR] 2.7, 95% confidence interval [95% CI] 1.2-5.9), as was being born > or =2 weeks preterm (RR 1.9, 95% CI 1.2-3.0); however, being breastfed was not (RR 0.8, 95% CI 0.6-1.1).Birth weight > or =10 pounds and preterm birth were both positively associated with incident SLE among women.
Exposure to cigarette smoke in utero - Comparison of reports from mother and daughter EPIDEMIOLOGY Simard, J. F., Rosner, B. A., Michels, K. B. 2008; 19 (4): 628-633
Smoking during pregnancy has been associated with asthma, obesity, and decreased cognitive functioning in the offspring. To study the role of in utero smoking exposure in offsprings' adult health outcomes, it may be necessary to rely upon reports by the offspring themselves.We studied 34,949 mother-daughter pairs participating in the Nurses' Health Study II for whom data on the daughter's early passive cigarette smoke exposure had been obtained from both mother and daughter. We calculated sensitivity and specificity of daughter's early exposure to smoke (using mother's report as the gold standard), as well as kappa statistics. Mother and daughter reports were also analyzed as risk factors for asthma and birthweight to demonstrate face validity.Sensitivity of daughters' reported prenatal exposure ranged from 74% to 85%, while specificity was between 90% and 95% (kappa = 0.72-0.81). Daughter's reported childhood exposure as a proxy for mother's report of smoking during pregnancy had a sensitivity of 89% and specificity of 88%. Results were similar for daughter's report of father's smoking during her childhood. Maternal smoking during pregnancy is consistently associated with reductions in offspring birthweight, and with asthma risk in offspring. The daughter's risk of being very low (<1500 g) or low birthweight (<2500 g) or of having asthma were similar when exposure was defined according to mother's report, daughter's report of fetal smoke exposure, and daughter's report of mother's smoking during childhood.Daughter's report of mother's smoking prenatally and in childhood are good proxy measures for mother's own report of smoking during pregnancy.
View details for DOI 10.1097/EDE.0b013e3181761cdb
What can epidemiology tell us about systemic lupus erythematosus? INTERNATIONAL JOURNAL OF CLINICAL PRACTICE Simard, J. F., Costenbader, K. H. 2007; 61 (7): 1170-1180
Systemic lupus erythematosus (SLE) is an often-severe autoimmune rheumatic disease most commonly diagnosed in women in their childbearing years. It is thought to develop when genetically predisposed individuals are exposed to one or more environmental triggers. This review outlines the epidemiologic evidence for several putative risk factors including cigarette smoke, hormonal and reproductive factors, environmental silica and infectious exposures, as well as many yet to be identified. We also review the evidence for factors associated with increased disease activity and adverse outcomes in SLE. We review the literature on the epidemiology of SLE, its distribution, potential risk factors for its onset and for adverse outcomes. The information considered in this review was gathered through extensive review of the literature. Online Pubmed literature searches, previous reviews of the epidemiology of SLE and original studies were employed. Epidemiologic studies have helped to identify some of these potential risk factors, including exogenous hormone use, cigarette smoking, infections such as Epstein-Barr virus (EBV) and crystalline silica exposure, but many more have yet to be studied. These exposures may interact with multiple genetic factors in determining susceptibility to SLE. While epidemiologic research has contributed an enormous amount to our understanding of the disease and its pathogenesis, there are many more avenues of epidemiologic research that deserve to be pursued.
Prevalent rheumatoid arthritis and diabetes among NHANES III participants aged 60 and older JOURNAL OF RHEUMATOLOGY Simard, J. F., Mittleman, M. A. 2007; 34 (3): 469-473
This study examines the cross-sectional association between prevalent rheumatoid arthritis (RA) and diabetes among noninstitutionalized US civilians aged >or= 60 years between 1988 and 1994.Using National Health and Nutrition Examination Survey III data from the National Center for Health Statistics, RA and diabetes were identified using several classification schemes. In total, 5302 survey participants aged >or= 60 years were included in logistic regression analyses taking survey weights into account. We also conducted sensitivity analyses restricting the study population to participants not recently prescribed glucocorticoids and fasting at least 8 hours prior to blood draw, as well as data incorporated from the Multiple Imputation Project.Among the 5302 participants aged >or= 60, 144 participants had RA and 24 of these also were found to have prevalent diabetes. The adjusted odds ratios for the cross-sectional association between RA and diabetes ranged from 1.1 to 1.5, but did not reach statistical significance.While this study cannot definitively rule out a modest non-null association, we can conclude that there is no evidence of a strong cross-sectional association between prevalent RA and diabetes in subjects aged >or= 60 years. Future longitudinal studies with more participants with RA are required to further evaluate a possible association between RA and the incidence of diabetes.
The large print giveth and the small print taketh away: Preemptive treatment of serologically active, clinically quiet systemic lupus erythematosus ARTHRITIS AND RHEUMATISM Liang, M. H., Simard, J. F. 2006; 54 (11): 3378-3380
Evidence for differential acquired drug resistance to anti-tumour necrosis factor agents in rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Finckh, A., Simard, J. F., Gabay, C., Guerne, P. 2006; 65 (6): 746-752
Acquired drug resistance or gradual drug failure has been described with most disease modifying antirheumatic drugs (DMARDs) and is also starting to be recognised with anti-tumour necrosis factor (anti-TNF) agents.To study acquired drug resistance to anti-TNF agents in rheumatoid arthritis (RA).Swiss health authorities requested continuous monitoring of patients receiving biological agents. Intensification of co-therapy with traditional DMARDs, gradual dose escalation, and drug discontinuation rates in all patients receiving infliximab, etanercept, or adalimumab, adjusting for potential confounders, were analysed. Intensification of DMARD co-therapy and time to discontinuation of the three anti-TNF agents were analysed using a proportional hazards models. Dose escalation and evolution of RA disease activity (DAS28) were analysed using a longitudinal regression model.1198 patients contributing 1450 patient-years of anti-TNF treatment met the inclusion criteria. The rate of intensification of traditional DMARD co-therapy over time was significantly higher with infliximab (hazards ratio = 1.73 (99% confidence interval (CI) 1.19 to 2.51)) than with the two other agents. Infliximab also showed significant dose escalation over time, with an average dose increase of +12% (99% CI 8% to 16%) after 1 year, and +18% (99% CI 11% to 25%) after 2 years. No significant differences in discontinuation rates were seen between the three anti-TNF agents (ANOVA, p = 0.67). Evolution of disease activity over time indicated a lower therapeutic response to infliximab (DAS28, p<0.001) compared with etanercept, after 6 months' treatment.In this population, infliximab was associated with a higher risk of requiring intensification of DMARD co-therapy than the other anti-TNF agents and a significant dose escalation over time. Analysis of RA disease activity indicated a reduced therapeutic response to infliximab after the first 6 months of treatment, suggestive of acquired drug resistance.
The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis - A population-based study ARTHRITIS AND RHEUMATISM Finckh, A., Simard, J. F., Duryea, J., Liang, M. H., Huang, J., Daneel, S., Forster, A., Gabay, C., Guerne, P. A. 2006; 54 (1): 54-59
To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage, in a population-based cohort. The 3 strategies were infliximab with concomitant disease-modifying antirheumatic drugs (DMARDs), etanercept with concomitant DMARDs, and etanercept alone.We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for >10 months. The rates of erosion progression and joint space narrowing (JSN) were analyzed using multivariate regression models for longitudinal data, with adjustment for potential confounders.A total of 372 patients treated with anti-tumor necrosis factor (TNF) therapies met the inclusion criteria. The baseline characteristics of the patients assigned to the 3 strategies were not significantly different, except that, as expected, more patients were receiving combination therapy with infliximab. The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression (P < 0.001), but the effectiveness of the 2 combination-treatment strategies was similar (P = 0.07). The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone (P = 0.04) or etanercept plus DMARDs (P = 0.02). Treatment with anti-TNF agents (infliximab or etanercept) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression (P = 0.045).When combined with traditional DMARDs, both etanercept and infliximab appear to offer similar protection against progressive structural joint damage, and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone.