Glinda S. Cooper

Understanding the Epidemiology and Progression of Systemic Lupus Erythematosus

OBJECTIVES This review examines the burden and patterns of disease in systemic lupus erythematosus (SLE) and the influence and interactions of gender, ethnicity, age, and psychosocial attributes with respect to disease progression, focusing on issues relevant to clinical practice and research. METHODS PubMed literature search complemented by review of bibliographies listed in identified articles. RESULTS An increased risk among reproductive age women is clearly seen in African Americans in the United States. However, in other populations, a different pattern is generally seen, with the highest age-specific incidence rates occurring in women after age 40 years. The disease is 2 to 4 times more frequent, and more severe, among nonwhite populations around the world and tends to be more severe in men and in pediatric and late-onset lupus. SLE patients now experience a higher than 90% survival rate at 5 years. The less favorable survival experience of ethnic minorities is possibly related to socioeconomic status rather than to ethnicity per se, and adequate social support has been shown to be a protective factor, in general, in SLE patients. Discordance between physician and patient ratings of disease activity may affect quality of care. CONCLUSIONS Our understanding of ways to improve outcomes in SLE patients could benefit from patient-oriented research focusing on many dimensions of disease burden. Promising research initiatives include the inclusion of community-based patients in longitudinal studies, use of self-assessment tools for rating disease damage and activity, and a focus on self-perceived disease activity and treatment compliance.

The epidemiology of autoimmune diseases.

Autoimmune diseases are among the leading causes of death among young and middle-aged women in the United States. Incidence rates vary among the autoimmune diseases, with estimates ranging from less than one newly-diagnosed case of systemic sclerosis to more than 20 cases of adult-onset rheumatoid arthritis per 100,000 person-years. Prevalence rates range from less than 5 per 100,000 (e.g. chronic active hepatitis, uveitis) to more than 500 per 100,000 (Grave disease, rheumatoid arthritis, thyroiditis). At least 85% of thyroiditis, systemic sclerosis, systemic lupus erythematosus, and Sjögren disease patients are female. Although most diseases can occur at any age, some diseases primarily occur in childhood and adolescence (e.g. type 1 diabetes), in the mid-adult years (e.g. myasthenia gravis, multiple sclerosis), or among older adults (e.g. rheumatoid arthritis, primary systemic vasculitis). Ethnic and geographic differences in incidence of specific autoimmune diseases have been documented, but specific groups may be at higher risk for some diseases and lower risk for other diseases. The incidence of type 1 diabetes increased but the rates of rheumatoid arthritis declined over the past 40 years. Thus although there are commonalities, there are also important demographic differences between diseases. Disease-specific research, as well as studies that focus on potentially related diseases, needs to be conducted.

Age at natural menopause and mortality.

PURPOSE The purpose of this study was to examine the association between age at menopause and mortality in a population-based sample of women in the United States. METHODS This study was based on data from the National Health and Examination Survey (NHANES) Epidemiologic Follow-up Study; 3191 women aged 50-86 years were included. There were 345 deaths over a mean follow-up time of 4.0 years. We used age-stratified and Poisson regression procedures to assess mortality risk by age at natural menopause, with adjustment for age, duration of follow-up, race, education, smoking, and use of hormone replacement therapy. We conducted a separate analysis for surgical menopause with bilateral oophorectomy. RESULTS Compared with women who were menstruating to age 50 or later, the adjusted mortality rate ratios (RR) were 1.50 (95% confidence interval (CI), 0.97-2.34) for women with a natural menopause at age < 40, 1.04 (95% CI, 0.72-1.51) for those with menopause at age 40-44, and 0.96 (95% CI, 0.72-1.26) for those with menopause at age 45-49. Women with a natural menopause at age 40-44 years experienced an increased risk of cancer-related mortality (adjusted RR 2.34, 95% CI, 1.20-4.58). No age-related increased mortality risk was seen among women who had surgical menopause with bilateral oophorectomy. CONCLUSIONS This study provides some support for the concept that age at natural menopause serves as a biological marker of health and aging, with potential implications extending beyond cardiovascular diseases.

Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States.

We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex and age in a population-based study of 265 SLE patients. Patients ful” lled the American College of Rheumatology classi” cation criteria. The median time between diagnosis and study enrollment was 13 months. The clinical and hematologic data were limited to occurrences up to 6 months after the diagnosis date, as documented in medical records. We used sera collected at study enrollment from 244 (92%) patients for serologic testing of autoantibodies. The associations between clinical and immunological features of SLE and age, sex and race were examined using logistic regression. The effect of each of these variables was examined adjusting for the other two demographic factors. Mean age at diagnosis was 6 years younger among African-Americans and other minorities compared with white patients (P < 0.01). Discoid lupus, proteinuria, anti-Sm and anti-RNP autoantibodieswere more commonly seen in African-American patients, with odds ratios higher than 3.0. Photosensitivity and mucosal ulcers were noted less often in African-American patients. Proteinuria, leukopenia, lymphopenia and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and antiDNA autoantibodies declined with age. The extent to which the differences we observed re‘ ect genetic or environmental in‘ uences on the disease process should be investigated.

A Promoter Haplotype of the Immunoreceptor Tyrosine-Based Inhibitory Motif-Bearing FcγRIIb Alters Receptor Expression and Associates with Autoimmunity. I. Regulatory FCGR2B Polymorphisms and Their Association with Systemic Lupus Erythematosus

FcγRIIb, the immunoreceptor tyrosine-based inhibitory motif-containing receptor for IgG (Mendelian Inheritance in Man no. 604590), plays an important role in maintaining the homeostasis of immune responses. We have identified 10 novel single-nucleotide polymorphisms in the promoter region of human FCGR2B gene and characterized two functionally distinct haplotypes in its proximal promoter. In luciferase reporter assays, the less frequent promoter haplotype leads to increased expression of the reporter gene in both B lymphoid and myeloid cell lines under constitutive and stimulated conditions. Four independent genome-wide scans support linkage of the human FcγR region to the systemic lupus erythematosus (SLE; Online Mendelian Inheritance in Man no. 152700) phenotype. Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054). The FCGR2B haplotype has no linkage disequilibrium with previously identified FCGR2A and FCGR3A polymorphisms, and after adjustment for FCGR2A and FCGR3A, FCGR2B showed a persistent association with SLE (odds ratio = 1.72; p = 0.0083). These results suggest that an expression variant of FCGR2B is a risk factor for human lupus and implicate FCGR2B in disease pathogenesis.

Occupational exposures and autoimmune diseases

Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely.

Menstrual and reproductive risk factors for ischemic heart disease

The role of hormones in ischemic heart disease is of considerable interest, but limited data are available pertaining to risk factors associated with endogenous hormones. We examined the association between menstrual and reproductive factors and ischemic heart disease in a cohort of 867 white, college-educated women who prospectively recorded menstrual cycle data for at least 5 years from their early 20s through their menopause. Ischemic heart disease history was obtained from a self-administered (N = 714) or proxy-administered (N = 153) questionnaire completed at a mean age of 73 years. The analysis included 44,899 person-years of follow-up and 45 cases of myocardial infarction, angioplasty, heart bypass surgery, or ischemic heart disease-related mortality. Ischemic heart disease risk decreased with increasing age at menarche (age-adjusted RR 0.76 per year, 95% CI = 0.60-0.95). Considering menstrual cycle characteristics ages 28-32, there was little overall association with length, variability, or bleeding duration. Ischemic heart disease risk increased with later age at first birth (age-adjusted RR 2.90 for ages 33-43 compared with 25-29) and later age at last birth (age-adjusted RR 3.79 for ages > or =40 compared with 35-39), but there was little association with high parity.

Human Health Effects of Dichloromethane: Key Findings and Scientific Issues

Background: The U.S. Environmental Protection Agency (EPA) completed a toxicological review of tetrachloroethylene (perchloroethylene, PCE) in February 2012 in support of the Integrated Risk Information System (IRIS). Objectives: We reviewed key findings and scientific issues regarding the human health effects of PCE described in the U.S. EPA’s Toxicological Review of Tetrachloroethylene (Perchloroethylene). Methods: The updated assessment of PCE synthesized and characterized a substantial database of epidemiological, experimental animal, and mechanistic studies. Key scientific issues were addressed through modeling of PCE toxicokinetics, synthesis of evidence from neurological studies, and analyses of toxicokinetic, mechanistic, and other factors (tumor latency, severity, and background rate) in interpreting experimental animal cancer findings. Considerations in evaluating epidemiological studies included the quality (e.g., specificity) of the exposure assessment methods and other essential design features, and the potential for alternative explanations for observed associations (e.g., bias or confounding). Discussion: Toxicokinetic modeling aided in characterizing the complex metabolism and multiple metabolites that contribute to PCE toxicity. The exposure assessment approach—a key evaluation factor for epidemiological studies of bladder cancer, non-Hodgkin lymphoma, and multiple myeloma—provided suggestive evidence of carcinogenicity. Bioassay data provided conclusive evidence of carcinogenicity in experimental animals. Neurotoxicity was identified as a sensitive noncancer health effect, occurring at low exposures: a conclusion supported by multiple studies. Evidence was integrated from human, experimental animal, and mechanistic data sets in assessing adverse health effects of PCE. Conclusions: PCE is likely to be carcinogenic to humans. Neurotoxicity is a sensitive adverse health effect of PCE. Citation: Guyton KZ, Hogan KA, Scott CS, Cooper GS, Bale AS, Kopylev L, Barone S Jr, Makris SL, Glenn B, Subramaniam RP, Gwinn MR, Dzubow RC, Chiu WA. 2014. Human health effects of tetrachloroethylene: key findings and scientific issues. Environ Health Perspect 122:325–334; http://dx.doi.org/10.1289/ehp.1307359

Risk factors for development of systemic lupus erythematosus: allergies, infections, and family history.

We examined risk factors for systemic lupus erythematosus (SLE) in 265 recently diagnosed patients in North Carolina and South Carolina and 355 control subjects identified through drivers license records and frequency matched to patients by age, sex, and state. Analyses were limited to exposures before diagnosis (cases) or reference year (control subjects). SLE patients were more likely than control subjects to report a history of allergy to medications (odds ratio [OR] 3.1, 95% confidence interval [CI], 2.1-4.5), particularly to antibiotics. SLE risk increased with history of shingles (OR 2.5, 95% CI 1.1-5.9) and with frequent (more than once per year) cold sores in the 3 years before diagnosis (OR 2.8, 95% CI 1.4-5.4). There was little association with history of mononucleosis, a marker of late infection with Epstein-Barr virus, implanted medical devices, or hepatitis B vaccination. History of lupus in parents or siblings was associated with an increased risk (OR 3.3, 95% CI 1.2-8.6). Further research is needed to clarify whether medication allergies and specific infectious agents are involved in the etiology of SLE. Published by Elsevier Science Inc.

Active and passive smoking and the occurrence of natural menopause.

We examined smoking in relation to natural menopause in 543 women who prospectively recorded menstrual data from their 20s. Mean age at natural menopause was 0.8 years younger (95% CL = -1.5, -0.0) in 98 women who smoked at menopause compared with 362 never-smokers (RR 1.3, 95% CI = 1.0-1.7). We did not observe a decrease in age at natural menopause in former smokers, a dose-response among current smokers, or a lower age at menopause with passive smoke exposure at home. These results suggest that the effect of smoking on ovarian senescence is limited to active smoking during the menopausal transition.