EBV infection and the immune response may be involved in the pathogenesis of rheumatoid arthritis (RA). Past studies have suggested an association between EBV and RA.
We studied the association between EBV serologies and RA risk in a nested case-control study in the Nurses’ Health Study cohorts. We confirmed incident RA cases from 1990–2002 by questionnaire and medical record review. Each incident case with blood collected prior to RA symptoms was matched to a healthy participant by time of day and date of blood collection, birth year, menopausal status and postmenopausal hormone use. Immunofluorescence assays measured serologic EBV responses: viral capsid antigen (VCA), early-antigen-diffuse (EA-D) and early antigen-complex (EA-restricted and diffuse), Epstein Barr nuclear antigen (EBNA)-1, EBNA-2 and cytomegalovirus (CMV), as control. All were reported as titers, except BZLF-1 and CMV, which were reported as positive or negative. ANA positive samples were excluded. Elevated EBV antibody titers were defined as the upper 20% (or nearest titer) among controls. Conditional logistic regression analyses modeled RA risk associated with elevated EBV titers or the presence/absence CMV, further adjusted for pack-years smoking and alcohol intake.
87 incident RA cases were identified. Mean time to RA after blood draw was 6.2 (±3.5) years in NHS and 1.9 (±0.6) years in NHSII. Antibody titers against EBV were not significantly different between pre-RA cases and controls.
In this prospective study of women, we observed no association between EBV serologies and RA risk.
rheumatoid arthritis; Epstein Barr virus; virus; risk factors; epidemiology
We evaluated the epidemiologic evidence that vitamin D may be related to human autoimmune disease risk.
PubMed limited to English from inception through April 2010 was searched using keywords: “vitamin D”, “autoimmune” and autoimmune disease names. We summarized in vitro, animal, and genetic association studies of vitamin D in autoimmune disease pathogenesis. We sorted studies by design and disease and performed a systematic review of: a) cross-sectional data concerning vitamin D level and autoimmune disease; b) interventional data on vitamin D supplementation in autoimmune diseases and c) prospective data linking vitamin D level or intake to autoimmune disease risk.
Vitamin D has effects on innate and acquired immune systems and vitamin D receptor polymorphisms have been associated with various autoimmune diseases. In experimental animal models, vitamin D supplementation can prevent or forestall autoimmune disease. We identified 76 studies in which vitamin D levels were studied in autoimmune disease patients, particularly with active disease, and compared to controls. Nineteen observational or interventional studies assessed the effect of vitamin D supplementation as therapy for various autoimmune diseases (excluding psoriasis and vitiligo) with a range of study approaches and results. The few prospective human studies performed conflict as to whether vitamin D level or intake is associated with autoimmune disease risk. No interventional trials have investigated whether vitamin D affects human autoimmune disease risk.
Cross-sectional data point to a potential role of vitamin D in autoimmune disease prevention, but prospective interventional evidence in humans is still lacking.
vitamin D; autoimmune disease; intake; risk factor; epidemiology; systematic review
We investigated nationwide prevalence, incidence, and sociodemographics of SLE and lupus nephritis among Medicaid-enrolled children.
Children aged 3 to <18 years with SLE (≥3 International Classification of Diseases, 9th Revision, codes of 710.0, all >30 days apart) were identified from Medicaid Analytic eXtract data (2000–2004), containing all inpatient and outpatient Medicaid claims for 47 U. S states and the District of Columbia. Lupus nephritis was identified from ≥2 ICD-9 billing codes >30 days apart for glomerulonephritis, proteinuria or renal failure. We calculated prevalence and incidence of SLE and lupus nephritis among Medicaid-enrolled children overall and within sociodemographic groups.
Of 30,420,597 Medicaid-enrolled children during these years, 2,959 with SLE were identified. SLE prevalence was 9.73 (95% CI 9.38 – 10.08) per 100,000. Of these, 84% were female, 40% African-American, 25% Hispanic and 21% White; 42% resided in the South. 1,106 (37%) of children with SLE had lupus nephritis: prevalence 3.64 (95% CI 3.43 – 3.86) per 100,000. The average annual incidence of SLE was 2.22 (95% CI 2.05–2.40) and that of lupus nephritis was 0.72 (95%CI 0.63– 0.83) cases per 100,000 Medicaid enrollees per year. Prevalence and incidence rates of lupus and lupus nephritis increased with age, were higher in girls than boys, and in all non-White than White racial/ethnic groups.
SLE prevalence and incidence rates among Medicaid-enrolled children in the U.S. are high compared to studies in other populations. These represent the first population-based estimates of lupus nephritis prevalence and incidence in the U.S. to date.
Systemic lupus erythematosus; pediatric; nephritis; incidence; prevalence; Medicaid; children; disparities
Quality indicators (QIs) for assessment of care of patients with systemic lupus erythematosus SLE) have been proposed. We evaluated care according to these proposed QIs for osteoporosis and cardiovascular disease (CVD) in patients with SLE in our rheumatology practice.
We selected 200 patients with SLE according to American College of Rheumatology (ACR) Criteria and ≥ 2 visits to our practice in 2007–8. We performed a structured medical record review and collected demographics, SLE and past medical history, medications, laboratories and data concerning osteoporosis and CVD management. We employed univariable analyses and multivariable regression analyses to test for factors associated with care meeting the proposed QIs.
94% of patients were female and 64% white. Mean age was 46.3 years and mean lupus duration was 15.3 years. 29% were taking ≥ 7.5 mg prednisone per day for ≥ 3 months. The proportions of patients for whom care met the proposed QIs were: 57% for bone mineral density (BMD) testing, 62% for calcium and vitamin D supplementation, and 86% for anti-resorptive or anabolic osteoporosis medications. Only 3% had 5 cardiac risk factors assessed within the year and 26% had 4 cardiac risk factors assessed annually. Smoking, fasting lipid panels and diabetes mellitus were rarely assessed annually. Having a primary care physician (PCP) within our healthcare network increased care meeting QIs.
Care according to newly proposed QIs for osteoporosis and CVD was suboptimal in our academic center. In order to standardize and improve care of patients with SLE, we suggest specific changes to the proposed QIs.
systemic lupus erythematosus; quality indicator; osteoporosis; cardiovascular disease; bone mineral density; screening; cholesterol; blood pressure; management; risk factor; calcium and vitamin D
Antioxidants may protect against development of rheumatoid arthritis or systemic lupus erythematosus by combating oxidative stress. The authors identified and confirmed incident cases of rheumatoid arthritis and systemic lupus erythematosus among 184,643 US women followed in the Nurses’ Health Study and Nurses’ Health Study II cohorts in 1980–2004. Semiquantitative food frequency questionnaires assessed intakes of vitamins A, C, and E and α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin from foods and supplements. The authors examined total antioxidant intake by calculating a “ferric-reducing ability of plasma” score, a new method for quantifying the total antioxidant effect of a food based on the reduction of ferric to ferrous iron by antioxidants. Cumulative updated total energy-adjusted dietary intakes were used. Associations between intake of each nutrient and incident rheumatoid arthritis and systemic lupus erythematosus were examined in age-adjusted and Cox proportional hazards models, adjusted for confounders. Results from the cohorts were pooled meta-analytically by using random-effects models. The authors identified 787 incident rheumatoid arthritis cases and 192 systemic lupus erythematosus cases for whom prospective dietary information was available. In these large, prospective cohorts of women, antioxidant intake was not associated with the risk of developing either rheumatoid arthritis or systemic lupus erythematosus.
antioxidants; arthritis, rheumatoid; diet; food; lupus erythematosus, systemic; risk factors; vitamins
Purpose of Review
Systemic lupus erythematosus (SLE), an inflammatory rheumatic disease characterized by autoantibody production and diverse clinical manifestations, disproportionately affects vulnerable groups: women, racial and ethnic minorities, the poor, and those lacking medical insurance and education. We summarize the current knowledge of the disparities observed in SLE and highlight recent research that aims to dissect the causes of these disparities and to identify the potentially modifiable factors contributing to them.
Several remediable causes, including lack of education, self-efficacy, and access to quality, experienced healthcare, have been found to contribute to observed disparities in SLE prevalence and outcomes.
SLE is associated with alarming disparities in incidence, severity and outcomes. The causes of these disparities are under study by several research groups. Identifying potentially correctable contributory factors should allow for the development of effective strategies to improve the healthcare delivery and outcomes in all SLE patients.
Systemic lupus erythematosus; health disparities; socioeconomic status; heath care access
Geographic variation in RA incidence in the United States is unknown.
We studied residential region from 1921–1976 and RA risk in a prospective cohort of women, the Nurses’ Health Study. Information on state of residence was collected at baseline in 1976 (ages 30–55), and on state at birth, at age 15, and at age 30 in 1992. Among 83,546 subjects reporting residence for all 4 time points, 706 incident RA cases from 1976–2004 were confirmed by screening questionnaire and record review for American College of Rheumatology criteria. Residential region was classified as: West, Midwest, Mid-Atlantic, New England, and Southeast. Multivariate cox proportional hazard models were used to assess relationships between region and RA risk, adjusting for age and smoking, body mass index, parity, breastfeeding, postmenopausal status, postmenopausal hormone use, father’s occupation, race, and physical activity. Analyses were performed in subjects who lived in the same regions, or moved, over time.
Compared to those in the West, women in New England had a 37–45% elevated risk of RA in multivariable models at each time point (eg. state in 1976: RR 1.42; 95% CI 1.10, 1.82). In analyses of women who lived in the same region at birth, age 15, and age 30, living in the Midwest was associated with greater risk (RR 1.47; 95% CI 1.05, 2.05), as was living in New England (RR 1.40; 95%CI 0.98, 2.00). Compared to living in the West at birth, age 15, and age 30, RA risk was higher in the East.
In this large cohort of American women, there was significant geographic variation in incident RA after controlling for confounders. Potential explanations include regional variation in behavioral factors, climate, environmental exposures, RA diagnosis, or genetic factors.
rheumatoid arthritis; risk factors; incidence; geography; air pollution
Little is known about patterns of use of initial kidney replacement therapies among patients with LN end-stage renal disease (LN ESRD). We aimed to identify sociodemographic and clinical factors associated with variation in initial kidney replacement therapies among LN ESRD patients.
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Data System. Age, sex, race, ethnicity, medical insurance, employment status, residential region, clinical factors and comorbidities were considered as potential predictors of ESRD treatment choice -- peritoneal dialysis (PD), hemodialysis (HD) or pre-emptive kidney transplantation -- in age-adjusted and multivariable-adjusted logistic regression analyses.
Of 11,317 individuals with incident LN ESRD, 82.0% initiated HD; 12.2% PD, and 2.8% underwent pre-emptive kidney transplantation. Receiving initial PD was significantly associated with earlier calendar year, female sex, higher albumin and hemoglobin, and lower serum creatinine levels. African Americans (vs. Whites), Medicaid beneficiaries and those with no health insurance (vs. private insurance), and those unemployed (vs. employed) had significantly reduced PD initiation. Comorbidities including congestive heart failure, peripheral vascular disease and inability to ambulate were also associated with decreased PD. Many sociodemographic and clinical factors favoring PD were associated with pre-emptive kidney transplant (vs. dialysis) as well.
Few patients with LN ESRD receive initial PD or pre-emptive kidney transplantation. Race, ethnicity, employment and medical insurance type are strongly associated with initial kidney replacement therapy choice. Future studies need to investigate the appropriateness of sociodemographic and clinical variation and the comparative effectiveness of kidney replacement therapies for LN ESRD.
peritoneal dialysis; hemodialysis; kidney transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
The pathogenesis of RA, a disabling autoimmune disease, is incompletely understood. Early in the development of RA there appears to be loss of immune homeostasis and regulation, and premature immunosenescence. While identification of risk factors and understanding of the phases of RA pathogenesis are advancing, means of accurately predicting an individual’s risk of developing RA are currently lacking. Telomere length has been proposed as a potential new biomarker for the development of RA that could enhance prediction of this serious disease. Studies examining telomere length in relation to RA have found that telomere erosion appears to proceed more rapidly in subjects with RA than in healthy controls, and that telomere lengths are shorter in those with the RA-risk HLA-shared epitope genes. These studies have been small, however, with retrospective or cross-sectional designs. The potential role of telomere shortening as an independent biomarker for future RA risk, perhaps strongly genetically determined by HLA-SE genes, after controlling for known risk factors such as smoking, body mass index and immunosuppressant medication use, as well as systemic inflammation, is an unanswered question.
immunosenescence; rheumatoid arthritis; telomere; biomarker; risk factor; aging; autoimmune
Little is known about the sociodemographic correlates of kidney transplantation and survival among U.S. children with lupus nephritis-associated ESRD. We aimed to identify predictors of listing for kidney transplantation (wait-listing), kidney transplantation, and mortality among children with lupus nephritis-associated ESRD.
Children aged 5–18 years with new onset lupus nephritis-associated ESRD were identified in the U.S. Renal Data System (1995–2006). We investigated demographic and clinical characteristics, causes of death and predictors of wait-listing, kidney transplantation, and mortality during the first 5 years of ESRD. Cox proportional hazards models were used.
583 children had incident lupus nephritis-associated ESRD. Mean age at ESRD onset was 16.2 years (SD 2.4); 51% were African American and 24% Hispanic. Within 5 years 292 (49%) were wait-listed, 193 (33%) received a kidney transplant and 131 (22%) died. Main causes of death were cardiopulmonary (31%) and infectious (16%). Children in the Northeast and West (vs. South) were more than twice as likely to be wait-listed (P<0.001, P<0.001) and over 50% more likely to be transplanted (P<0.04). There were fewer kidney transplants among older vs. younger (OR 0.59, P=0.009), African American vs. white (OR 0.48, P<0.001), Hispanic vs. non-Hispanic (OR 0.63, P=0.03) children, and those with Medicaid vs. private insurance (OR 0.7, P=0.03). Mortality was almost double among African American vs. white children (OR 1.83, P<0.001).
Among U.S. children with lupus nephritis-associated ESRD age, race, ethnicity, insurance and geographic region were associated with significant variation in 5-year wait-listing for kidney transplant, kidney transplantation and mortality.
Systemic Lupus Erythematosus; Pediatric Rheumatology; Nephritis; Survival; End Stage Renal Disease; Children; Disparities; Outcomes
It is unknown whether recent advances lupus nephritis (LN) treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to LN, or in the characteristics, therapies, and outcomes of patients with LN ESRD.
Patients with incident LN ESRD (1995–2006) were identified in the US Renal Datasystem. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses.
12,344 incident cases of LN ESRD were identified. Mean age at ESRD onset was 41 years; 81.6% were female and 49.5% African American. SIRs for LN ESRD among those ages 5–39, African Americans, and in the US Southeast increased significantly from 1995–2006. Increases in body mass index and the prevalence of both diabetes and hypertension were detected. Mean serum hemoglobin at ESRD onset increased, while that of serum creatinine decreased over time. More patients used hemodialysis and fewer peritoneal dialysis. There was a slight increase in pre-emptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first three years of ESRD declined. Mortality did not change over 12 years of study.
The characteristics of LN ESRD patients and their initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans and in the South, outcomes did not improve in over a decade of evaluation.
incidence; dialysis; transplantation; survival; lupus; nephritis; end-stage renal disease; chronic kidney disease; systemic lupus erythematosus; African American; Hispanic; race; women
To examine the association between alcohol consumption and markers of inflammation in pre-clinical rheumatoid arthritis (RA) patients.
We studied 174 incident RA cases with stored blood collected 1–16 years prior to RA symptoms (“pre-clinical RA”) from the Nurses’ Health Study. Alcohol intake was measured using a detailed food frequency questionnaire every two years prior to blood collection. Plasma was tested for biomarkers of inflammation: high-sensitivity C-reactive protein (hsCRP), anti–cyclic citrullinated peptide (anti-CCP) antibodies, interleukin-6 (IL-6) and soluble tumor necrosis factor receptor II (sTNFRII). Generalized additive models were used to uncover structure in the relationship between each biomarker and cumulative average alcohol intake. Then general linear models were used for multivariable adjusted analyses with appropriate polynomial terms of alcohol consumption.
After controlling for age at blood collection, smoking, parity and duration of breastfeeding, menopausal status, oral contraceptive use, BMI and the time between blood collection and RA onset, we found that the daily alcohol consumption showed a U-shaped association with IL-6 levels in RA patents prior to symptoms. We also found an inverse relationship between alcohol intake and sTNFRII levels but no associations with hsCRP and anti-CCP levels.
Alcohol consumption was associated with markers of inflammation including IL-6 and sTNFRII in RA patients prior to symptoms.
The SLICC Damage Index (SDI) is a validated instrument for assessing organ damage in systemic lupus erythematosus (SLE). Trained physicians must complete it, limiting utility where this is impossible.
We developed and pilot-tested a self-assessed organ damage instrument, the Lupus Damage Index Questionnaire (LDIQ), in 37 SLE subjects and 7 physicians. After refinement, 569 English-speaking SLE subjects and 14 rheumatologists from 11 international SLE clinics participated in validation. Subjects and physicians completed instruments separately. We calculated sensitivity, specificity, Spearman correlations and agreement, using the SDI as gold standard. 605 SLE participants in the community-based National Data Bank for Rheumatic Diseases (NDB) study completed the LDIQ and we assessed correlations with outcome and disability measures.
Mean LDIQ score was 3.3 (0-16) and mean SDI score was 1.5 (0-9). LDIQ had a moderately high correlation with SDI (Spearman r=0.50, p<0.001). Specificities of individual LDIQ items were >80%, except for neuropathy. Sensitivities were variable and lowest for damage with <1% prevalence. Agreement between SDI and LDIQ was > 85% for all but neuropathy, reduced renal function, deforming arthritis and alopecia. In the NDB, LDIQ correlated well with comorbidity index (r=0.45), SF-36 physical component scale (0.43), Medical Research Council dyspnea scale (0.40), disability (0.37) and SLE Activity Questionnaire score (0.37).
The LDIQ’s metric properties are good compared to the SDI. It has construct validity and correlations with health assessments similar to the SDI. The LDIQ should allow expansion of SLE research. Its ultimate value will be determined in longitudinal studies.
systemic lupus erythematosus; questionnaire; damage; SLICC damage index; validation; self-assessed
Cumulative genetic profiles can help identify individuals at high-risk for developing RA. We examined the impact of 39 validated genetic risk alleles on the risk of RA phenotypes characterized by serologic and erosive status.
We evaluated single nucleotide polymorphisms at 31 validated RA risk loci and 8 Human Leukocyte Antigen alleles among 542 Caucasian RA cases and 551 Caucasian controls from Nurses' Health Study and Nurses' Health Study II. We created a weighted genetic risk score (GRS) and evaluated it as 7 ordinal groups using logistic regression (adjusting for age and smoking) to assess the relationship between GRS group and odds of developing seronegative (RF− and CCP−), seropositive (RF+ or CCP+), erosive, and seropositive, erosive RA phenotypes. In separate case only analyses, we assessed the relationships between GRS and age of symptom onset.
In 542 RA cases, 317 (58%) were seropositive, 163 (30%) had erosions and 105 (19%) were seropositive with erosions. Comparing the highest GRS risk group to the median group, we found an OR of 1.2 (95% CI = 0.8–2.1) for seronegative RA, 3.0 (95% CI = 1.9–4.7) for seropositive RA, 3.2 (95% CI = 1.8–5.6) for erosive RA, and 7.6 (95% CI = 3.6–16.3) for seropositive, erosive RA. No significant relationship was seen between GRS and age of onset.
Results suggest that seronegative and seropositive/erosive RA have different genetic architecture and support the importance of considering RA phenotypes in RA genetic studies.
To test for an association between periodontal disease (PD) and incident rheumatoid arthritis (RA) in a large prospective cohort.
We conducted a prospective analysis of history of periodontal surgery, tooth loss and risk of RA among 81,132 women in the Nurses’ Health Study prospective cohort. Periodontal surgery and tooth loss were used as proxies for history of PD. There were 292 incident RA cases diagnosed from 1992 to 2004. Information on periodontal surgery and tooth loss in the past two years was collected by questionnaire in 1992. Cox proportional hazards models were used to assess relationships between periodontal surgery, tooth loss and RA risk adjusting for age, smoking, number of natural teeth, BMI, parity, breastfeeding, postmenopausal status, postmenopausal hormone use, father’s occupation and alcohol intake.
Compared with those who reported no history of periodontal surgery or tooth loss, women with periodontal surgery or tooth loss did not have a significantly elevated risk of RA in multivariable-adjusted models (RR=1.24; 95% CI (0.83, 1.83) and RR=1.18; 95% CI (0.47, 2.95), respectively). In analyses stratified by ever and never smokers, ever smokers with periodontal surgery had an increased risk that was also non-significant. Those with severe PD (both history of periodontal surgery and tooth loss) did not have a significant increased risk.
In this large cohort of U.S. women, there is no evidence of an increased risk of later onset RA among those with a history of periodontal surgery and/or tooth loss.
Rheumatoid Arthritis; periodontal disease; tooth loss; periodontitis; oral health; inflammation
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
One’s own cigarette smoking is a risk factor for systemic lupus erythematosus (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 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 (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 does not increase the risk of adult-onset SLE in women.
Anti-cyclic citrullinated peptide (anti-CCP) antibodies are strongly associated with increased risk of rheumatoid arthritis (RA). While the anti-CCP level is commonly dichotomized for clinical use, the best threshold for and utility of the titer as a continuous variable to predict development of RA are uncertain.
Using data from the Nurses’ Health Study and Nurses’ Health Study II longitudinal cohorts, we examined the sensitivity, specificity, and hazard of RA at various thresholds of the anti-CCP. Incident RA was confirmed using the Connective Tissue Disease Screening Questionnaire and medical record review in 93 women from among 62,437 participants with blood samples. Three controls per case were randomly chosen, matching on cohort, age, and menopausal status. Stored plasma was tested for anti-CCP antibodies with the second-generation Diastat™ ELISA. Five threshold values were assessed for sensitivity, specificity, and time to diagnosis of RA. Hazard of RA was assessed with conditional logistic regression models adjusting for smoking and reproductive factors.
Using the suggested threshold of > 5 U/ml for anti-CCP positivity, specificity was 100%, but sensitivity was only 28%. A threshold of > 2 U/ml had a higher sensitivity (51%), and similar specificity (80%), with an odds ratio of 11.2 (95% confidence interval 4.7–26.9) for RA. Anti-CCP level as an ordinal variable was strongly associated with time to RA onset, with higher values predicting shorter time to RA onset.
A lower threshold for anti-CCP positivity was more sensitive in predicting RA development. Higher ranges of the level were informative in predicting time to RA onset.
RHEUMATOID ARTHRITIS; ANTI-CYCLIC CITRULLINATED PEPTIDE; STATISTICAL METHODS
Previous studies have reported an interaction between ever cigarette smoking and the presence of the HLA-DRB1 shared epitope (SE) genotype and RA risk. To address the effect of dosage, we conducted a case control study nested within two prospective cohorts to determine the interaction between heavy smoking and the HLA-SE.
Blood was obtained from 32,826 women in the Nurses’ Health Study and 29,611 women in the Nurses’ Health Study II. Incident RA diagnoses were validated by chart review. Controls were matched on age, menopausal status, and postmenopausal hormone use. High resolution HLA-DRB1 genotyping was performed for SE alleles. HLA-SE, smoking, and HLA-SE *smoking interactions, and RA risk, were assessed using conditional logistic regression models, adjusted for age and reproductive factors. We tested for additive and multiplicative interactions.
439 Caucasian matched pairs were included. Mean age at RA diagnosis was 55.2 years; 62% of cases were seropositive. We observed a modest additive interaction between ever smoking and HLA-SE in seropositive RA risk. We found a strong additive interaction (attributable proportiondue to interaction(AP) = 0.50; p = 0.0002) between heavy smoking and any HLA-SE in seropositive RA risk, and significant multiplicative interaction (p = 0.05). The highest risk was in heavy smokers with double copy HLA-SE (OR 7.47 [95% CI, 2.77–20.11]).
We observed a strong gene-environment interaction between HLA-SE and smoking when stratifying by pack-years of smoking rather than by ever smoking. Future studies should assess cumulative exposure to cigarette smoke when testing for gene-smoking interactions.
rheumatoid arthritis; gene-environment interaction; HLA; smoking
Increasingly, assays for the detection of anti-citrullinated peptide antibodies (ACPA) are used in RA diagnosis. This review summarizes the biologic basis and development of ACPA assays, available ACPA assays and their performance characteristics, and diagnostic properties of ACPA alone and compared to rheumatoid factor (RF) in early RA. We also review correlations, precision, costs and cost-effectiveness, availability, stability and reproducibility of the available assays. Taken together, data indicate that ACPA has a higher specificity than RF for early RA, good predictive validity, high sensitivity, apparent cost-effectiveness and good stability and reproducibility. Given its superior performance characteristics and increasing availability, ACPA is emerging as the most useful single assay for the diagnosis of RA.
anti-citrullinated peptide antibody; rheumatoid factor; anti-CCP; ACPA; RF; diagnosis; rheumatoid arthritis; early arthritis
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 two 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, being breastfed, and its duration, adjusting for potential confounders. Random effects meta-analytic methods were used to compute combined estimates from the two cohorts.
We found no statistically significant association between preterm birth and incident RA (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 breastfeeding duration.
In these cohorts of women, neither being preterm birth nor breastfed were associated with the onset of RA.
Classification of rheumatoid arthritis (RA) is increasingly important as new therapies can halt the disease in its early stages. Antibodies to cyclic citrullinated peptides (anti-CCP) are widely used for RA diagnosis, but are not in the 1987 American College of Rheumatology (ACR) Criteria for RA Classification. We developed and tested the performance characteristics of new criteria for RA classification, incorporating anti-CCP.
We identified all subjects seen in our Arthritis Center with rheumatoid factor (RF) and anti-CCP tested simultaneously between January 1 and June 30, 2004 and reviewed their medical records for the ACR criteria, rheumatologists' diagnoses, RF and anti-CCP. We revised the ACR criteria in two ways: (1) adding anti-CCP, (2) replacing rheumatoid nodules and erosions with anti-CCP (CCP 6 criteria). We compared sensitivity and specificity of all criteria, in all subjects and in subjects with arthritis symptoms ≤ 6 months.
Medical records of 292 subjects were analysed: mean age was 54 years, 82% were women, and mean symptom duration was 4.1 years. 17% were RF+ and 14% were anti-CCP+ at initial testing. 78 (27%) had definite RA per treating rheumatologist at latest follow-up.
The CCP 6 criteria increased sensitivity for RA classification for all subjects regardless of symptom duration: 74% vs. 51% for ACR criteria with a loss in specificity (81% vs. 91%). Sensitivity was greatly improved in subjects with symptoms ≤ 6 months: 25% vs. 63% for ACR criteria with a decrease in specificity.
The CCP 6 criteria improved upon the sensitivity of the ACR criteria, most remarkably for subjects with symptoms ≤ 6 months and could be used for classification of subjects for RA in clinical studies.
Rheumatoid arthritis; cyclic citrullinated peptide; classification; early RA