Bio

Academic Appointments


Professional Education


  • 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)

Teaching

2013-14 Courses


Publications

Journal Articles


  • 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

    Abstract

    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

    View details for Web of Science ID 000316824000022

    View details for PubMedID 23160780

  • Reply. Arthritis and rheumatism Simard, J. F., Neovius, M., Askling, J. 2013; 65 (6): 1671-1672

    View details for DOI 10.1002/art.37929

    View details for PubMedID 23508884

  • 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

    Abstract

    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.

    View details for DOI 10.1002/acr.21883

    View details for PubMedID 23139229

  • 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

    Abstract

    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

    View details for Web of Science ID 000317578300001

    View details for PubMedID 23568792

  • 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

    Abstract

    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

    View details for Web of Science ID 000317620500007

    View details for PubMedID 23486550

  • 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. A., Geborek, P., Jacobsson, L. T., Askling, J., Neovius, M. 2013

    Abstract

    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.

    View details for PubMedID 23520035

  • 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): 870-8

    Abstract

    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.

    View details for PubMedID 23281173

  • 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

    Abstract

    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.

    View details for DOI 10.1002/art.34582

    View details for Web of Science ID 000310544500004

    View details for PubMedID 22886739

  • 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

    Abstract

    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.

    View details for DOI 10.3899/jrheum.120493

    View details for Web of Science ID 000310256100010

    View details for PubMedID 22859356

  • 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

    Abstract

    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

    View details for Web of Science ID 000308233500010

    View details for PubMedID 22815381

  • 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

    View details for Web of Science ID 000308634100003

    View details for PubMedID 22956591

  • 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

    Abstract

    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.

    View details for DOI 10.1111/j.1365-2796.2011.02475.x

    View details for Web of Science ID 000305510600005

    View details for PubMedID 22026548

  • 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

    Abstract

    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.

    View details for DOI 10.1136/annrheumdis-2011-200947

    View details for Web of Science ID 000305293400016

    View details for PubMedID 22504565

  • 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

    Abstract

    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.

    View details for DOI 10.1002/art.30654

    View details for Web of Science ID 000298598100007

    View details for PubMedID 21898355

  • 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)

    Abstract

    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

    View details for Web of Science ID 000311025900005

    View details for PubMedID 22390680

  • 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

    Abstract

    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.

    View details for DOI 10.1111/j.1600-6143.2011.03704.x

    View details for Web of Science ID 000296335800024

    View details for PubMedID 21883909

  • 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

    Abstract

    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

    View details for Web of Science ID 000292188100011

    View details for PubMedID 21518724

  • 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

    Abstract

    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.

    View details for DOI 10.1002/art.30247

    View details for Web of Science ID 000292809700009

    View details for PubMedID 21305513

  • 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

    Abstract

    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.

    View details for DOI 10.1136/ard.2010.136812

    View details for Web of Science ID 000290149900021

    View details for PubMedID 21406455

  • 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

    Abstract

    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.

    View details for DOI 10.1136/ard.2010.133371

    View details for Web of Science ID 000287965400011

    View details for PubMedID 21149495

  • 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

    Abstract

    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.

    View details for DOI 10.1136/ard.2010.130914

    View details for Web of Science ID 000286927800019

    View details for PubMedID 21081525

  • 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

    Abstract

    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

    View details for Web of Science ID 000285193500028

    View details for PubMedID 21084326

  • 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

    Abstract

    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.

    View details for DOI 10.1111/j.1600-6143.2010.03367.x

    View details for Web of Science ID 000285783500021

    View details for PubMedID 21199354

  • 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

    Abstract

    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

    View details for Web of Science ID 000287645500002

    View details for PubMedID 20955087

  • 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

    Abstract

    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.

    View details for DOI 10.1002/art.27741

    View details for Web of Science ID 000285210200031

    View details for PubMedID 20827782

  • 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

    Abstract

    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

    View details for Web of Science ID 000284181800014

    View details for PubMedID 20430581

  • 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

    Abstract

    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

    View details for DOI 10.1136/ard.2009.115535

    View details for Web of Science ID 000276982300011

    View details for PubMedID 19762360

  • 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

    Abstract

    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.

    View details for DOI 10.3899/jrheum.090237

    View details for Web of Science ID 000273749900007

    View details for PubMedID 19833745

  • 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

    View details for Web of Science ID 000266735700011

    View details for PubMedID 19455057

  • 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

    Abstract

    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.

    View details for DOI 10.1136/ard.2007.080937

    View details for Web of Science ID 000264196000011

    View details for PubMedID 18593757

  • 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

    Abstract

    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.

    View details for DOI 10.1177/0961203308098186

    View details for Web of Science ID 000265552000009

    View details for PubMedID 19318396

  • 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

    Abstract

    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.

    View details for PubMedID 19275685

  • 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)

    Abstract

    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.

    View details for DOI 10.1186/ar2878

    View details for Web of Science ID 000278282100026

    View details for PubMedID 20003285

  • Perinatal factors and adult-onset lupus ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Simard, J. F., Karlson, E. W., Costenbader, K. H., Hernan, M. A., Stampfer, M. J., Liang, M. H., Mittleman, M. A. 2008; 59 (8): 1155-1161

    Abstract

    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.

    View details for DOI 10.1002/art.23930

    View details for Web of Science ID 000258888800014

    View details for PubMedID 18668600

  • 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

    Abstract

    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

    View details for Web of Science ID 000256865100020

    View details for PubMedID 18467961

  • 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

    Abstract

    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.

    View details for DOI 10.1111/j.1742-1241.2007.01434.x

    View details for Web of Science ID 000247319600019

    View details for PubMedID 17577298

  • 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

    Abstract

    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.

    View details for Web of Science ID 000244613800006

    View details for PubMedID 17183622

  • 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

    View details for DOI 10.1002/art.22199

    View details for Web of Science ID 000241981800002

    View details for PubMedID 17075813

  • 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

    Abstract

    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.

    View details for DOI 10.1136/ard.2005.045062

    View details for Web of Science ID 000237513300009

    View details for PubMedID 16339288

  • 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

    Abstract

    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.

    View details for Web of Science ID 000234605200008

    View details for PubMedID 16385495

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