WASF3 disrupts mitochondrial respiration and may mediate exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by various disabling symptoms including exercise intolerance and is diagnosed in the absence of a specific cause, making its clinical management challenging. A better understanding of the molecular mechanism underlying this apparent bioenergetic deficiency state may reveal insights for developing targeted treatment strategies. We report that overexpression of Wiskott-Aldrich Syndrome Protein Family Member 3 (WASF3), here identified in a 38-y-old woman suffering from long-standing fatigue and exercise intolerance, can disrupt mitochondrial respiratory supercomplex formation and is associated with endoplasmic reticulum (ER) stress. Increased expression of WASF3 in transgenic mice markedly decreased their treadmill running capacity with concomitantly impaired respiratory supercomplex assembly and reduced complex IV levels in skeletal muscle mitochondria. WASF3 induction by ER stress using endotoxin, well known to be associated with fatigue in humans, also decreased skeletal muscle complex IV levels in mice, while decreasing WASF3 levels by pharmacologic inhibition of ER stress improved mitochondrial function in the cells of the patient with chronic fatigue. Expanding on our findings, skeletal muscle biopsy samples obtained from a cohort of patients with ME/CFS showed increased WASF3 protein levels and aberrant ER stress activation. In addition to revealing a potential mechanism for the bioenergetic deficiency in ME/CFS, our study may also provide insights into other disorders associated with fatigue such as rheumatic diseases and long COVID.

Attitudes and Perceptions Toward Authorized Deception: A Pilot Comparison of Healthy Controls and Fibromyalgia Patients.

OBJECTIVE: Little is known about the perceptions and attitudes of participants who volunteer in studies involving authorized deception. Thus, this cross-sectional pilot study measured, for the first time, the perceptions about participation in an authorized-deception placebo analgesia study in chronic pain patients with fibromyalgia and assessed whether their perceptions differed from healthy controls. METHODS: An anonymous survey with questions about trust in research and willingness to participate in future research involving deception was mailed to participants in both groups after completion of the parent study. Statistical analyses were performed using the Mann-Whitney U and chi-square tests (31 controls and 16 fibromyalgia patients were included in the analyses). RESULTS: The majority of participants expressed little or no concern about the deception, still trusted the scientific process, and found the debriefing procedure helpful and worthwhile. Group differences were found in willingness to 1) participate in the parent study had the deceptive element been disclosed in advance (controls = definitely, fibromyalgia patients = probably, U = 341.5, P = 0.01) and 2) participate in future studies (controls = definitely, fibromyalgia patients = probably, U = 373, P < 0.001). CONCLUSIONS: Despite slightly less favorable responses of fibromyalgia patients and the relatively small size of the study, these findings suggest that attitudes and perceptions about participating in an authorized placebo study remain positive in both healthy and chronic pain populations.

Human Leukocyte Antigen Shared Epitope and Inflammation, Cardiovascular Disease, Cancer, and Mortality Among Postmenopausal Women in the Women's Health Initiative Rheumatoid Arthritis Study.

Specific alleles of the human leukocyte antigen (HLA)-DRB1 gene (HLA-DRB1) encode a "shared epitope" (SE) associated with rheumatoid arthritis (RA), especially more severe cyclic-citrullinated peptide antibody-positive (anti-CCP+) RA. We evaluated associations of number of SE alleles (0, 1, or 2) with total and cardiovascular disease (CVD) mortality and incident coronary heart disease (CHD), CVD, and cancer over a mean 8.9 (standard deviation, 3.5) years of follow-up, stratifying by baseline anti-CCP status (positive (+) vs. negative (-)). A longitudinal study, the Women's Health Initiative RA Study (1993-2010), sampled postmenopausal women who reported RA at baseline (1993-1998) or follow-up in the Women's Health Initiative, classified as anti-CCP+ RA (n = 556) or anti-CCP- non-RA (n = 1,070). Among anti-CCP+ RA women, SE alleles were not related to age-adjusted risks of CHD, CVD, or cancer or to total or CVD mortality. Among anti-CCP- non-RA women, age-adjusted hazard ratios for 1 and 2 SE alleles versus 0 SE alleles were 0.41 (95% confidence interval (CI): 0.34, 0.50) and 0.44 (95% CI: 0.27, 0.72), respectively, for CVD; 0.43 (95% CI: 0.37, 0.53) and 0.30 (95% CI: 0.16, 0.64), respectively, for CHD; and 0.62 (95% CI: 0.53, 0.73) and 0.52 (95% CI: 0.33, 0.83), respectively, for cancer. Associations persisted after adjustment for CVD risk factors, joint pain, rheumatoid factor positivity, and inflammatory markers (white blood cell count or cytokine level). In future studies, investigators should evaluate SE associations among anti-CCP- adults without RA and potential mechanisms.

Rheumatoid arthritis in the Women's Health Initiative: methods and baseline evaluation.

Second-generation assays for anti-cyclic citrullinated peptide (anti-CCP), a highly sensitive and specific marker for rheumatoid arthritis (RA), have redefined the epidemiology of RA. In the Women's Health Initiative (WHI) RA study (2009-2011), we evaluated the prevalence of anti-CCP positivity among 15,691 (10.2% of 161,808) WHI participants aged 50-79 years who reported RA. Using stored baseline specimens, we measured serum anti-CCP, rheumatoid factor (RF), and antinuclear antibody in a defined sample of 9,988 of black, white, and Hispanic women. In a subset of women, we measured plasma cytokine levels and number of copies of the human leukocyte antigen (HLA)-DRB1 (HLA-DRB1) shared epitope in DNA by means of Luminex polymerase chain reaction typing (Luminex Corporation, Austin, Texas). We validated classification of probable clinical RA in 2 clinics as anti-CCP positivity or self-reported validated use of disease-modifying antirheumatic drugs (DMARDs). The prevalence of anti-CCP positivity was 8.1%, and the prevalence of RF positivity was approximately 16.0%. DMARD use including prednisone was reported by 1,140 (11.4%) participants (841 excluding prednisone) but by 57.5% of anti-CCP-positive women. The prevalence of 2 shared epitopes was also much higher for anti-CCP-positive women (18.2%, as opposed to only 5.5% for women with anti-CCP-negative DMARD-positive RA and 6.6% for anti-CCP-negative, RF-negative DMARD nonusers). Median cytokine levels were much higher for anti-CCP-positive/RF-positive women. Women with anti-CCP-positive RA and anti-CCP-negative RA had different characteristics with regard to HLA shared epitope, cigarette smoking, and inflammation (cytokines).

Life Events, Caregiving, and Risk of Autoimmune Rheumatic Diseases in the Women's Health Initiative Observational Study.

OBJECTIVE: Growing evidence suggests psychosocial stressors may increase risk of developing autoimmune disease. We examined stressful life events and caregiving in relation to incident rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in the Women's Health Initiative Observational Study cohort. METHODS: The sample of postmenopausal women included 211 incident RA or SLE cases reported within 3 years after enrollment, confirmed by use of disease-modifying antirheumatic drugs (i.e., probable RA/SLE), and 76,648 noncases. Baseline questionnaires asked about life events in the past year, caregiving, and social support. We used Cox regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs), adjusting for age, race/ethnicity, occupational class, education, pack-years of smoking and BMI. RESULTS: Incident RA/SLE was associated with reporting 3 or more life events (e.g., age-adjusted HR 1.70 [95% CI 1.14, 2.53]; P for trend = 0.0026). Elevated HRs were noted for physical (HR 2.48 [95% CI 1.02, 6.04]) and verbal (HR 1.34 [0.89, 2.02]) abuse (P for trend = 0.0614), 2 or more interpersonal events (HR 1.23 [95% CI 0.87, 1.73]; P for trend = 0.2403), financial stress (HR 1.22 [95% CI 0.90, 1.64]), and caregiving 3 or more days per week (HR 1.25 [95% CI 0.87, 1.81]; P for trend = 0.2571). Results were similar, excluding women with baseline symptoms of depression or moderate-to-severe joint pain in the absence of diagnosed arthritis. CONCLUSION: Our findings support the idea that diverse stressors may increase risk of developing probable RA or SLE in postmenopausal women, supporting the need for further studies in autoimmune rheumatic diseases, including childhood adverse events, life event trajectories, and modifying psychosocial and socioeconomic factors.

Optimism, pessimism, cynical hostility, and biomarkers of metabolic function in the Women's Health Initiative.

BACKGROUND: Psychological attitudes reflecting expectations about the future (optimism, pessimism) and people (cynical hostility) independently predict incident cardiovascular disease and possibly diabetes, but underlying biologic pathways are incompletely understood. Herein we examined the cross-sectional relationship between optimism, pessimism, and cynicism and biomarkers of metabolic function in the Women's Health Initiative. METHODS: Among 3443 postmenopausal women, biomarkers of metabolic function (fasting insulin [FINS] and glucose) were measured at baseline and used to calculate insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) and pancreatic ß-cell activity (homeostasis model assessment of ß-cell function [HOMA-B]). Psychological attitudes were assessed by the Life Orientation Test, Revised (full scale, and optimism and pessimism subscales) and the Cook-Medley cynicism subscale. Multivariable linear regression modeled the association of psychological attitudes with biomarker levels, adjusting for sociodemographics, health conditions, and health behaviors. Because obesity promotes insulin resistance and obese individuals tend to report higher levels of pessimism and cynical hostility, an interaction with body mass index (BMI) was explored. RESULTS: In fully adjusted models, only pessimism remained independently associated with higher FINS and insulin resistance (HOMA-IR). Scoring 1 point higher on the pessimism subscale was associated with a 1.2% higher FINS, whereas scoring 1 SD higher was associated with a 2.7% higher FINS (P = 0.03); results were similar for HOMA-IR. An interaction term with BMI was not significant. CONCLUSIONS: In multivariable models, higher dispositional pessimism was associated with worse metabolic function; these findings were not modified by obesity status. Results extend prior work by linking pessimism to an objective biomarker of insulin resistance in elderly women.

The Use of Polysymptomatic Distress Categories in the Evaluation of Fibromyalgia (FM) and FM Severity.

OBJECTIVE: The polysymptomatic distress (PSD) scale is derived from variables used in the 2010 American College of Rheumatology (ACR) fibromyalgia (FM) criteria modified for survey and clinical research. The scale is useful in measuring the effect of PSD over the full range of pain-related clinical symptoms, not just in those who are FM criteria-positive. However, no PSD scale categories have been defined to distinguish severity of illness in FM or in those who do not satisfy the FM criteria. We analyzed the scale and multiple covariates to develop clinical categories and to further validate the scale. METHODS: FM was diagnosed according to the research criteria modification of the 2010 ACR FM criteria. We investigated categories in a large database of patients with pain (2732 with rheumatoid arthritis) and developed categories by using germane clinic variables that had been previously studied for severity groupings. By definition, FM cannot be diagnosed unless PSD is at least 12. RESULTS: Based on population categories, regression analysis, and inspections of curvilinear relationships, we established PSD severity categories of none (0-3), mild (4-7), moderate (8-11), severe (12-19), and very severe (20-31). Categories were statistically distinct, and a generally linear relationship between PSD categories and covariate severity was noted. CONCLUSION: PSD categories are clinically relevant and demonstrate FM type symptoms over the full range of clinical illness. Although FM criteria can be clinically useful, there is no clear-cut symptom distinction between FM (+) and FM (-), and PSD categories can aid in more effectively classifying patients.

Rheumatoid Arthritis, Anti-Cyclic Citrullinated Peptide Positivity, and Cardiovascular Disease Risk in the Women's Health Initiative.

OBJECTIVE: To evaluate the incidence of cardiovascular disease (CVD) morbidity and mortality over the course of 10 years among the more than 160,000 postmenopausal women in the Women's Health Initiative (WHI) in relation to self-reported rheumatoid arthritis (RA), taking disease-modifying antirheumatic drugs (DMARDs), anti-cyclic citrullinated peptide (anti-CCP) positivity, rheumatoid factor (RF) positivity, CVD risk factors, joint pain, and inflammation (white blood cell count and interleukin-6 levels). METHODS: Anti-CCP and RF were measured in a sample of WHI participants with self-reported RA (n = 9,988). RA was classified as self-reported RA plus anti-CCP positivity and/or taking DMARDs. Anti-CCP-negative women with self-reported RA and not taking DMARDs were classified as having "unverified RA." RESULTS: Age-adjusted rates of coronary heart disease (CHD), stroke, CVD, fatal CVD, and total mortality were higher in women with RA than in women with no reported RA, with multivariable-adjusted hazard ratios of 1.46 (95% confidence interval [95% CI] 1.17-1.83) for CHD and 2.55 (95% CI 1.86-3.51) for fatal CVD. Among women with RA, anti-CCP positivity and RF positivity were not significantly associated with higher risk of any outcomes, despite slightly higher risk of death for those who were anti-CCP positive than for those who were anti-CCP negative. Joint pain severity and CVD risk factors were strongly associated with CVD risk, even in women with no reported RA. CVD incidence was increased in women with RA versus women with no reported RA at almost all risk factor levels, except for low levels of joint pain or inflammation. Among women with RA, inflammation was more strongly associated with fatal CVD and total mortality than with CHD or CVD. CONCLUSION: Among postmenopausal women, RA was associated with 1.5-2.5-fold higher CVD risk. CVD risk was strongly associated with CVD risk factors, joint pain severity, and inflammation, but not with anti-CCP positivity or RF positivity.

Symptoms, the nature of fibromyalgia, and diagnostic and statistical manual 5 (DSM-5) defined mental illness in patients with rheumatoid arthritis and fibromyalgia.

PURPOSE: To describe and evaluate somatic symptoms in patients with rheumatoid arthritis (RA) and fibromyalgia, determine the relation between somatization syndromes and fibromyalgia, and evaluate symptom data in light of the Diagnostic and Statistical Manual-5 (DSM-5) criteria for somatic symptom disorder. METHODS: We administered the Patient Health Questionnaire-15 (PHQ-15), a measure of somatic symptom severity to 6,233 persons with fibromyalgia, RA, and osteoarthritis. PHQ-15 scores of 5, 10, and 15 represent low, medium, and high somatic symptom severity cut-points. A likely somatization syndrome was diagnosed when PHQ-15 score was ≥10. The intensity of fibromyalgia diagnostic symptoms was measured by the polysymptomatic distress (PSD) scale. RESULTS: 26.4% of RA patients and 88.9% with fibromyalgia had PHQ-15 scores ≥10 compared with 9.3% in the general population. With each step-wise increase in PHQ-15 category, more abnormal mental and physical health status scores were observed. RA patients satisfying fibromyalgia criteria increased from 1.2% in the PHQ-15 low category to 88.9% in the high category. The sensitivity and specificity of PHQ-15≥10 for fibromyalgia diagnosis was 80.9% and 80.0% (correctly classified = 80.3%) compared with 84.3% and 93.7% (correctly classified = 91.7%) for the PSD scale. 51.4% of fibromyalgia patients and 14.8% with RA had fatigue, sleep or cognitive problems that were severe, continuous, and life-disturbing; and almost all fibromyalgia patients had severe impairments of function and quality of life. CONCLUSIONS: All patients with fibromyalgia will satisfy the DSM-5 "A" criterion for distressing somatic symptoms, and most would seem to satisfy DSM-5 "B" criterion because symptom impact is life-disturbing or associated with substantial impairment of function and quality of life. But the "B" designation requires special knowledge that symptoms are "disproportionate" or "excessive," something that is uncertain and controversial. The reliability and validity of DSM-5 criteria in this population is likely to be low.

Social security work disability and its predictors in patients with fibromyalgia.

OBJECTIVE: To determine prevalence and incidence of US Social Security Disability and Supplemental Security Income (SSD) in patients with fibromyalgia and to investigate prediction of SSD. METHODS: Over a mean of 4 years (range 1-13 years), we studied 2,321 patients with physician-diagnosed fibromyalgia (prevalent cases) and applied modified American College of Rheumatology (ACR) 2010 research criteria to identify criteria-positive patients. RESULTS: During the study, 34.8% (95% confidence interval [95% CI] 32.9-36.8%) of fibromyalgia patients received SSD. The annual incidence of SSD among patients not receiving SSD at study enrollment was 3.4% (95% CI 3.0-3.9%), and 25% were estimated to be work disabled at 9.0 years of followup. By comparison, the prevalence of SSD in rheumatoid arthritis (RA) patients with concomitant fibromyalgia was 55.6% (95% CI 54.3-57.0%) and was 42.4% in osteoarthritis (OA). By study conclusion, 31.4% of SSD awardees were no longer receiving SSD. In univariate models, incident SSD in patients with fibromyalgia was predicted by sociodemographic measures and by symptom burden; but the strongest predictor was functional status (Health Assessment Questionnaire disability index [HAQ DI]). In multivariable models, the HAQ DI and the Short Form 36-item health survey physical and mental component summary scores, but no other variables, predicted SSD. Fibromyalgia criteria-positive patients had more SSD, but the continuous scale, polysymptomatic distress index derived from the ACR criteria was a substantially better predictor of SSD than a criteria-positive diagnosis. CONCLUSION: The prevalence of SSD is high in fibromyalgia, but not higher than in RA and OA patients who satisfy fibromyalgia criteria. The best predictors of work disability are functional status variables.

Fibromyalgia and physical trauma: the concepts we invent.

Despite weak to nonexistent evidence regarding the causal association of trauma and fibromyalgia (FM), literature and court testimony continue to point out the association as if it were a strong and true association. The only data that appear unequivocally to support the notion that trauma causes FM are case reports, cases series, and studies that rely on patients' recall and attribution - very low-quality data that do not constitute scientific evidence. Five research studies have contributed evidence to the FM-trauma association. There is no scientific support for the idea that trauma overall causes FM, and evidence in regard to an effect of motor vehicle accidents on FM is weak or null. In some instances effect may be seen to precede cause. Alternative causal models that propose that trauma causes "stress" that leads to FM are unfalsifiable and unmeasurable.

Polysymptomatic distress in patients with rheumatoid arthritis: understanding disproportionate response and its spectrum.

OBJECTIVE: Fibromyalgia (FM) in rheumatoid arthritis (RA) can cause consternation because symptoms are seen to be out of proportion to physician and laboratory assessments, and composite RA activity scores such as the 28 joint Disease Activity Score, Clinical Disease Activity Index, and Routine Assessment of Patient Index Data 3 (RAPID-3) can yield apparently "wrong" results. We explored the effect of polysymptomatic distress (PSD), a measure of fibromyalgianess and a quantity derived from the American College of Rheumatology 2010 FM diagnostic criteria, to explain the relationship of patient to physician variables. METHODS: We obtained PSD scores on 300 RA patients prior to ordinary clinical care, and assessed the associations of PSD with tender and swollen joints, physician global estimate of RA activity, pain, Health Assessment Questionnaire score, and composite RA activity measures during routine clinic assessments. RESULTS: PSD scores greater than the sample mean (8.8) were associated with increased patient symptoms regardless of the presence or absence of FM, while scores below the mean were associated with better patient outcomes. PSD scores predicted all patient outcomes and less strongly predicted physician outcomes. The discrepancy between patient and physician measures was greatest at low levels of physician-estimated disease activity. CONCLUSION: PSD rather than FM diagnosis more usefully identifies and predicts disproportionate responses. Just as there are patients who lean disproportionately toward greater severity, there are also patients who disproportionately report milder symptoms. Composite measures used to assess RA are flawed, as they confound RA inflammation and patient distress, and more consideration should be given to disaggregated assessments. PSD also appears to be influenced weakly by RA disease activity.

Determinants of mortality among postmenopausal women in the women's health initiative who report rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) patients have an increased risk of cardiovascular disease (CVD) and mortality. We measured anti-cyclic citrullinated peptide (anti-CCP) antibody levels and determined use of disease-modifying antirheumatic drugs (DMARDs) among women in the Women's Health Initiative (WHI). Using these data, we undertook this study to assess total mortality over 10 years of followup among white, black, or Hispanic women with self-reported RA in the WHI. METHODS: Using stored baseline serum, we measured anti-CCP, rheumatoid factor (RF), and antinuclear antibodies (ANAs) in 9,988 women who reported having RA. Based on a previous chart review study, probable RA was defined as either self-reported RA and anti-CCP positivity, or anti-CCP negativity and DMARD use. Cox proportional hazards regression was used to model the relationship of self-reported RA, DMARD exposure, and anti-CCP positivity to total mortality, using followup data through April 2009. RESULTS: At baseline, the mean age was 62.8 years; 24.5% of subjects were black and 10% were Hispanic. Prevalence of anti-CCP positivity was 8.1% (n = 812), and 217 women were anti-CCP negative but had reported use of DMARDs; therefore, 1,029 women (of 9,988) were classified as having probable RA, and 8,958 were classified as unlikely to have RA (with data on DMARD use missing for 1 subject). Age-adjusted mortality rates were ∼2-fold higher for anti-CCP-positive women, with 20.2 deaths per 1,000 person-years, as compared to 11.4 deaths per 1,000 person-years among anti-CCP-negative women with self-reported RA who never used DMARDs. Among women who did not report any arthritis at baseline, we found 8.3 deaths per 1,000 person-years. The increased risk among anti-CCP-positive women with RA was not explained by age, RF positivity, ANA positivity, or DMARD use. CONCLUSION: Anti-CCP-positive RA was associated with substantial excess mortality among postmenopausal women in the WHI. This result was not explained by the risk factors we measured.

The development of fibromyalgia--I: examination of rates and predictors in patients with rheumatoid arthritis (RA).

We determined rates and predictors of future development of fibromyalgia in patients with rheumatoid arthritis (RA). After excluding patients with fibromyalgia and those with high levels of fibromyalgia symptoms (fibromyalgianess score>10) at baseline, we studied fibromyalgia development in 9739 RA patients during 42,591 patient-years of follow-up. We defined fibromyalgia using a modification of the ACR 2010 fibromyalgia criteria. We used Cox regression to predict future fibromyalgia, and examined the accuracy of predictions using Harrell's C concordance coefficient. At the last observation, 7.4% of patients satisfied criteria, although 19.8% satisfied criteria at some point during follow-up, an incidence rate of 5.3 (95% CI 5.1, 5.6) per 100 patients years, and at rates that were similar in men (7.0%) and women (8.1%). Among those satisfying criteria, during 11,363 years of follow-up from the time of first fibromyalgia diagnosis, half of follow-up time was fibromyalgia+and was associated with markedly abnormal RA variable and FM variable scores. Demographic factors were weak predictors of fibromyalgia (C=0.604). Demographic plus RA variables (C=0.720) and demographic plus fibromyalgia variables (C=0.765), and all predictors (C=0.782) increased accuracy. Clinically important hazard ratios were noted for cognition, depression, comorbidity, and high levels of RA and FM continuous variables Overall, study results indicate that multiple, inter-correlated factors that include social disadvantage, psychological distress, comorbidity, RA severity, and fibromyalgia variables predict future development of fibromyalgia, but there is little evidence of the effect of underlying causes. After diagnosis, patients move in both directions across the diagnostic criteria cut points.

Arthritis increases the risk for fractures--results from the Women's Health Initiative.

OBJECTIVE: To examine the relationship between arthritis and fracture. METHODS: Women were classified into 3 self-reported groups at baseline: no arthritis (n = 83,295), osteoarthritis (OA; n = 63,402), and rheumatoid arthritis (RA; n = 960). Incident fractures were self-reported throughout followup. Age-adjusted fracture rates by arthritis category were generated, and the Cox proportional hazards model was used to test the association between arthritis and fracture. RESULTS: After an average of 7.80 years, 24,137 total fractures were reported including 2559 self-reported clinical spinal fractures and 1698 adjudicated hip fractures. For each fracture type, age-adjusted fracture rates were highest in the RA group and lowest in the nonarthritic group. After adjustment for several covariates, report of arthritis was associated with increased risk for spine, hip, and any clinical fractures. Compared to the nonarthritis group, the risk of sustaining any clinical fracture in the OA group was HR 1.09 (95% CI 1.05, 1.13; p < 0.001) and HR 1.49 (95% CI 1.26, 1.75; p < 0.001) in the RA group. The risk of sustaining a hip fracture was not statistically increased in the OA group (HR 1.11; 95% CI 0.98, 1.25; p = 0.122) compared to the nonarthritis group; however, the risk of hip fracture increased significantly (HR 3.03; 95% CI 2.03, 4.51; p < 0.001) in the RA group compared to the nonarthritis group. CONCLUSION: The increase in fracture risk confirms the importance of fracture prevention in patients with RA and OA.

Insecticide use and risk of rheumatoid arthritis and systemic lupus erythematosus in the Women's Health Initiative Observational Study.

OBJECTIVE: Farming and agricultural pesticide use has been associated with 2 autoimmune rheumatic diseases, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, risk associated with other residential or work place insecticide use is unknown. METHODS: We analyzed data from the Women's Health Initiative Observational Study (n=76,861 postmenopausal women, ages 50-79 years). Incident cases (n=213: 178 for RA, 27 for SLE, and 8 for both) were identified based on self-report and use of disease-modifying antirheumatic drugs at year 3 of followup. We examined self-reported residential or work place insecticide use (personally mixing/applying by self and application by others) in relation to RA/SLE risk, overall and in relation to farm history. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were adjusted for age, race, region, education, occupation, smoking, reproductive factors, asthma, other autoimmune diseases, and comorbidities. RESULTS: Compared with never used, personal use of insecticides was associated with increased RA/SLE risk, with significant trends for greater frequency (HR 2.04, 95% CI 1.17-3.56 for ≥6 times/year) and duration (HR 1.97, 95% CI 1.20-3.23 for ≥20 years). Risk was also associated with long-term insecticide application by others (HR 1.85, 95% CI 1.07-3.20 for ≥20 years) and frequent application by others among women with a farm history (HR 2.73, 95% CI 1.10-6.78 for ≥6 times/year). CONCLUSION: These results suggest residential and work place insecticide exposure is associated with the risk of autoimmune rheumatic diseases in postmenopausal women. Although these findings require replication in other populations, they support a role for environmental pesticide exposure in the development of autoimmune rheumatic diseases.

Validation of self-report of rheumatoid arthritis and systemic lupus erythematosus: The Women's Health Initiative.

OBJECTIVE: The Women's Health Initiative (WHI), initiated in 1993, enrolled 161,808 postmenopausal women aged 50-79 years and followed them with annual questionnaires for 8 years in order to study major causes of morbidity and mortality. Our objective was to determine the most effective and efficient means to validate self-reported rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in the WHI. METHODS: Data from 2 of 40 WHI clinical centers were used. Of these 7443 women, 643 self-reported RA and 106 self-reported SLE. Research coordinators contacted these women using mailers and telephone calls to obtain medical record releases and a Connective Tissue Screening Questionnaire (CSQ). Medical records were obtained on 286 self-reported RA and 34 self-reported SLE and reviewed by 3 rheumatologists blind to the self-reported diagnoses. Sensitivity, specificity, and the kappa statistic were computed to evaluate the level of agreement between self-report and chart review. RESULTS: Self-reported RA was accurate only 14.7% (42/286 cases) of the time. Coupling the self-report to medication data improved the positive predictive value (PPV; 62.2%) and kappa (0.53), suggesting a moderate agreement to chart review. Self-reported SLE was accurate only 11.8% (4/34 cases) of the time. Coupling the self-report to medication data improved the PPV (40.0%) and kappa (0.44), suggesting a moderate agreement to chart review. The CSQ was inferior to using medication data but was substantially better than self-report alone. CONCLUSION: The performance of disease self-report coupled with medication history in validating RA and SLE was very good and should obviate the need for time-consuming medical record reviews.