Objective. To evaluate levels of biomarkers in preclinical rheumatoid arthritis (RA) and to use elevated biomarkers to develop a model for the prediction of time to future diagnosis of seropositive RA.Methods. Stored samples obtained from 73 military cases with seropositive RA prior to RA diagnosis and from controls (mean 2.9 samples per case; samples collected a mean of 6.6 years prior to diagnosis) were tested for rheumatoid factor (RF) isotypes, anti-cyclic citrullinated peptide (anti-CCP) antibodies, 14 cytokines and chemokines (by bead-based assay), and C-reactive protein (CRP).Results. Preclinical positivity for anti-CCP and/or >2 RF isotypes was >96% specific for future RA. In preclinical RA, levels of the following were positive in a significantly greater proportion of RA cases versus controls: interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor 2, flt-3 ligand, tumor necrosis factor ␣, interferon-␥-inducible 10-kd protein, granulocyte-macrophage colony-stimulating factor, and CRP. Also, increasing numbers of elevated cytokines/chemokines were present in cases nearer to the time of diagnosis. RA patients who were >40 years old at diagnosis had a higher proportion of samples positive for cytokines/chemokines 5-10 years prior to diagnosis than did patients who were <40 years old at diagnosis (P < 0.01). In regression modeling using only case samples positive for autoantibodies highly specific for future RA, increasing numbers of cytokines/chemokines were predictive of decreased time to diagnosis, and the predicted time to diagnosis based on cytokines/chemokines was longer in older compared with younger cases.Conclusion. Levels of autoantibodies, cytokines/ chemokines, and CRP are elevated in the preclinical period of RA development. In preclinical autoantibodypositive cases, the number of elevated cytokines/ chemokines is predictive of the time of diagnosis of future RA in an age-dependent manner.Multiple studies have demonstrated that levels of disease-related biomarkers may be elevated prior to the onset of symptomatic rheumatoid arthritis (RA). These biomarkers include rheumatoid factor (RF) and antibodies to citrullinated protein antigens, as well as secre-

Corresponding author: V. Michael Holers, MD, Division of Rheumatology, University of Colorado at Denver and Health Sciences Center, Barbara Davis Center, 1775 North Ursula Street, Aurora, Colorado 80045, Phone: (303) Fax: (303) 724-7581, Michael.Holers@uchsc.edu. Address for reprint requests: Same as above * These two authors contributed equally to the study. COMPETING INTERESTSThe authors declare that they have no competing interests. AUTHORS' CONTRIBUTIONSDM participated in the design and analysis of this study and the writing of this manuscript. KD participated in the analysis of data and preparation of manuscript. LP participated in the analysis of samples and data and preparation of manuscript. AB and AL contributed statistical expertise in the analysis of data for this manuscript. CW participated in subject evaluation and determination of eligibility for this study MR participated in the design of this study and procurement of the serum samples for analysis WG participated in the design of this study and procurement of the serum samples for analysis, as well as subject evaluation and determination of eligibility for this study. JN participated in the design and analysis of this study and preparation of manuscript. VMH participated in the design and analysis of this study, antibody testing, and manuscript preparation. DISCLAIMERThe views expressed in this abstract are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or U.S. Government.The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive license (or non-exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article to be published in Annals of Rheumatic Diseases editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our license http://ard.bmjjournals.com/ifora/licence.pdf. Objectives-This study investigated factors that may influence the prevalence and timing of appearance of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies during the pre-clinical phase of rheumatoid arthritis (RA) development. NIH Public AccessMethods-243 serial pre-diagnosis serum samples from 83 subjects with RA were examined for the presence of RF and anti-CCP antibodies.Results-57% and 61% of subjects had at least one pre-diagnosis sample positive for RF or anti-CCP, respectively. Gender and race were not significantly associated with the prevalence or timing of pre-clinical antibody appearance. Pre-clinical anti-CCP positivity was strongly associated with the development of erosive RA (OR 4.64; 95% CI 1.71-12.63; p=0.003), but RF was not (p=0.11). Additionally, as age at the time of diagnosis of RA increased the duration of pre-diagnosis antibody positivity for RF and anti-CCP increased, with the longest duration of preclinical antibody positivity seen in patients diagnosed with RA over the age of 40. In ...

Background Adults with interstitial lung disease (ILD) often have serologic evidence of autoimmunity of uncertain significance without overt autoimmune disease. We examined associations of rheumatoid arthritis (RA)-associated antibodies with subclinical ILD in community-dwelling adults. Methods We measured serum rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAA; CT attenuation values between −600 and −250 HU) on cardiac CT in 6,736 community-dwelling U.S. adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILA) in 2,907 full-lung CTs at 9.5-year median follow-up. We used generalized linear and additive models to examine associations between autoantibodies and both HAA and ILA, and tested for effect modification by smoking. Results In adjusted models, HAA increased by 0.49% (95% CI 0.11–0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50–1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3–20%) per RF IgA doubling. Smoking modified the associations of both RF IgM and anti-CCP with both HAA and ILA (interaction p-values varied from 0.01 to 0.09). Among ever smokers, HAA increased by 0.81% (95% CI 0.33–1.30%) and ILA prevalence increased by 14% (95% CI 5–24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45–2.18%) and ILA prevalence increased by 13% (95% CI 2–24%) per anti-CCP doubling. Among never smokers, no meaningful associations were detected. Conclusions RA-related autoimmunity is associated with both quantitative and qualitative subclinical ILD phenotypes on CT, particularly among ever smokers.

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Background Previous studies have suggested an inverse relationship between physical activity and markers of inflammation such as high-sensitivity C-reactive protein (hs-CRP). However, these were inconsistent, and few examined whether race and gender influenced the relationship. This study determined a cross-sectional association between physical activity and hs-CRP level in 6142 middle-aged white, Chinese, black, and Hispanic participants enrolled in the Multi Ethnic Study of Atherosclerosis in 2000–2002. Methods Combined moderate and vigorous physical activity was measured by self-reported leisure, conditioning, occupational, and household activities. ANCOVA was used to assess the association between moderate/vigorous physical activity and hs-CRP by gender and race. Results Hs-CRP was higher in women. Blacks had the highest hs-CRP, and Chinese participants had the lowest. Hs-CRP decreased across tertiles of moderate/vigorous physical activity in Hispanic men in models adjusted for age, education, study site, and physical activity questionnaire mode of administration (p=0.005) and further adjusted for smoking, infection, and aspirin use (p=0.020). The trend remained significant after further adjustment for BMI; blood pressure; low-density lipoprotein cholesterol; high-density lipoprotein cholesterol; diabetes; and the use of antihypertensive, statin, and diabetes medication (p=0.044). There was a downward trend in hs-CRP across tertiles of physical activity in black and white men, but the association was weaker. No clear trend was observed in any female racial/ethnic groups. Conclusions These findings suggest that the association between moderate/vigorous physical activity and hs-CRP differs by race and gender. Further studies are needed to confirm this and to examine the mechanisms for these race and gender differences.

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Local interactions between (bio)chemicals and biological interfaces play an important role in fields ranging from surface patterning to cell toxicology. These interactions can be studied using microfluidic systems that operate in the “open space”, that is, without the need for the sealed channels and chambers commonly used in microfluidics. This emerging class of techniques localizes chemical reactions on biological interfaces or specimens without imposing significant “constraints” on samples, such as encapsulation, pre‐processing steps, or the need for scaffolds. They therefore provide new opportunities for handling, analyzing, and interacting with biological samples. The motivation for performing localized chemistry is discussed, as are the requirements imposed on localization techniques. Three classes of microfluidic systems operating in the open space, based on microelectrochemistry, multiphase transport, and hydrodynamic flow confinement of liquids are presented.

Objectives: To examine whether oral contraceptive use is associated with the presence of serum rheumatoid factor in women of reproductive age without rheumatoid arthritis. Methods: 304 women selected from parents of children who were at increased risk of developing type 1 diabetes were studied, because they were enriched with the human leucocyte antigen-DR4 allele, a susceptibility marker for both type 1 diabetes and rheumatoid arthritis. Participants visited a clinic where blood was drawn for rheumatoid factor testing, and exposure data were collected via questionnaires. A medical history and joint examination were performed to rule out rheumatoid arthritis. Participants and examiners were unaware of the participants' rheumatoid factor status at the time of examination and questionnaire. Results: Use of oral contraceptives at any time was inversely associated with rheumatoid factor positivity (adjusted odds ratio (OR) 0.2, 95% confidence interval (CI) 0.07 to 0.52) independent of age, education and smoking. Smoking >20 pack-years was also associated with rheumatoid factor positivity (adjusted OR 56.38, 95% CI 4.31 to 736.98) compared with never smoking. Smoking 1-19 pack-years was not associated with a positive rheumatoid factor. Conclusions: Our results suggest that oral contraceptive use, and possibly cigarette smoking, act early in the development of the immune dysregulation that occurs in rheumatoid arthritis. R heumatoid factor is a well-established test used in the diagnosis and prognosis of rheumatoid arthritis. In addition, rheumatoid factor precedes rheumatoid arthritis, and individuals with stable increases in rheumatoid factor have an increased incidence of rheumatoid arthritis, 1 suggesting that factors regulating rheumatoid factor production may have an important early role in the pathogenesis of rheumatoid arthritis.Specific major histocompatibility complex class II molecule DRB1 alleles encoding the shared epitope are the most important genetic risk factors for the development of rheumatoid arthritis.2 However, most individuals carrying the shared epitope do not develop rheumatoid arthritis, suggesting that a genetic predisposition is necessary but not sufficient for disease.Several epidemiological studies have investigated the association between oral contraceptives and rheumatoid arthritis. [3][4][5][6][7]