Darcy S. Majka

The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner.

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-1α (IL-1α), IL-1β, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, fibroblast growth factor 2, flt-3 ligand, tumor necrosis factor α, interferon-γ-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 autoantibody-positive cases, the number of elevated cytokines/chemokines is predictive of the time of diagnosis of future RA in an age-dependent manner.

Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis

Objectives: To investigate factors that may influence the prevalence and timing of appearance of rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies during the preclinical phase of rheumatoid arthritis (RA) development. Methods: 243 serial prediagnosis serum samples from 83 subjects with RA were examined for the presence of RF and anti-CCP antibodies. Results: Of the 83 cases, 47 (57%) and 51 (61%) subjects had at least one prediagnosis sample positive for RF or anti-CCP, respectively. Gender and race were not significantly associated with the prevalence or timing of preclinical antibody appearance. Preclinical anti-CCP positivity was strongly associated with the development of erosive RA (odds ratio = 4.64; 95% confidence interval 1.71 to 12.63; p<0.01), but RF was not (p = 0.60). Additionally, as age at the time of diagnosis of RA increased the duration of prediagnosis 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 no subjects did symptom onset precede the appearance of RF or anti-CCP antibodies. Conclusions: The period of time that RF and anti-CCP are present before diagnosis lengthens as the age at the time of diagnosis of RA increases. This finding suggests that factors such as genetic risk or environmental exposure influencing the temporal relationship between the development of RA-related autoantibodies and clinically apparent disease onset may differ with age.

Physical Activity and High-Sensitivity C-Reactive Protein: The Multi-Ethnic Study of Atherosclerosis

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.

Rheumatoid arthritis-associated autoantibodies and subclinical interstitial lung disease: the Multi-Ethnic Study of Atherosclerosis

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 anticyclic citrullinated peptide antibody (anti-CCP) and high attenuation areas (HAAs; CT attenuation values between −600 and −250 Hounsfield units) on cardiac CT in 6736 community-dwelling US adults enrolled in the Multi-Ethnic Study of Atherosclerosis. We measured interstitial lung abnormalities (ILAs) in 2907 full-lung CTs at 9.5-year median follow-up. We used generalised 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% to 0.86%) per doubling of RF IgM and by 0.95% (95% CI 0.50% to 1.40%) per RF IgA doubling. ILA prevalence increased by 11% (95% CI 3% to 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% to 1.30%) and ILA prevalence increased by 14% (95% CI 5% to 24%,) per RF IgM doubling; and HAA increased by 1.31% (95% CI 0.45% to 2.18%) and ILA prevalence increased by 13% (95% CI 2% to 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.

Is preclinical autoimmunity benign?: The case of cardiovascular disease.

Although there are many examples of autoantibodies in disease-free individuals, they can be a preclinical phenomenon heralding future autoimmune rheumatic disease. They may be a marker for autoreactive B-cell activation and other inflammatory autoimmune processes. The increased prevalence of cardiovascular disease (CVD) in autoimmune rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus, and the increased risk of CVD in patients with rheumatic disease with autoantibodies, suggest that CVD may have autoimmune features. Autoantibodies might be risk markers for subclinical and clinical CVD development not only in patients with rheumatic diseases but in the general population as well.

Rheumatoid Factors Are Associated with Subclinical and Clinical Atherosclerosis in African American Women: The Multi-Ethnic Study of Atherosclerosis (MESA)

Although the association between rheumatoid arthritis (RA) and cardiovascular disease (CVD) is established, the exact mechanism is unknown. We tested the hypothesis that RA‐related autoantibodies are independent risk factors for subclinical atherosclerosis and subsequent clinical CVD events.

Association of Rheumatoid Factors With Subclinical and Clinical Atherosclerosis in African American Women: The Multiethnic Study of Atherosclerosis: Atherosclerosis and RF in African American Women

Although the association between rheumatoid arthritis (RA) and cardiovascular disease (CVD) is established, the exact mechanism is unknown. We tested the hypothesis that RA‐related autoantibodies are independent risk factors for subclinical atherosclerosis and subsequent clinical CVD events.

415 SPECIFIC CYTOKINE AND CHEMOKINE INCREASES PRECEDE THE APPEARANCE OF ANTI-CYCLIC CITRULLINATED PROTEIN ANTIBODIES AND RHEUMATOID FACTOR IN THE PRECLINICAL PERIOD OF RHEUMATOID ARTHRITIS DEVELOPMENT.

Purpose To determine the relationship between cytokine/chemokine changes and the appearance of rheumatoid arthritis (RA)-related antibodies prior to the onset of clinically apparent RA. Methods Sixteen military subjects with rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP)-positive RA were selected from a larger cohort with stored prediagnosis serum samples. Cases were selected if they had two prediagnosis serum samples for analysis, the earliest of which (median 4.2 years prior to diagnosis) was anti-CCP negative. Nine of 16 of these earliest samples were also negative for RF (nephelometry and ELISA for IgM, IgA, IgG). The following cytokines and chemokines were measured with a bead-based multiplex assay: eotaxin (CCL11), IL-1α, GM-CSF, MCP-1 (CCL2), IL-β, FGF-2, IL-15, Flt-3 ligand, TNF-α, IL-6, IL-10, IP-10 (CXCL10), IL-12 p 70, IL-12 p40, and RANTES. Levels in RA cases were compared with military controls matched for age, gender, race, region of assignment, and length of sample storage. Wilcoxon signed-rank testing was performed for comparisons (SAS 9.1). Results Eotaxin, IL-1α, GM-CSF, and MCP-1 levels were significantly higher in the earliest preclinical RA case samples versus controls. In the 9 cases whose initial sample was negative for anti-CCP and RF, IL-1α was elevated versus controls (p = .04). Conclusions Cytokine/chemokine abnormalities can be detected prior to the development of anti-CCP and RF antibodies in individuals who later develop seropositive RA. These elevations may reflect asymptomatic synovial inflammation or undetected extra-articular inflammatory disease, each of which may lead to humoral autoimmune responses. Additional studies in preclinical RA are key to understanding the temporal and causal relationships between cytokine/chemokine dysregulation, RA-related autoimmunity, and development of clinically apparent disease.